2-(2,4,5-substituted-anilino) pyrimidine compounds

ABSTRACT

The present invention relates to certain 2-(2,4,5-substituted-anilino)pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exon19 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.

This application claims the benefit under 35 U.S.C. §119(e) ofApplication No. US61/512,061, filed 27 Jul. 2011 and US61/591,363, filed27 Jan. 2012.

The present invention relates to certain2-(2,4,5-substituted-anilino)pyrimidine compounds and pharmaceuticallysalts thereof which may be useful in the treatment or prevention of adisease or medical condition mediated through certain mutated forms ofepidermal growth factor receptor (for example the L858R activatingmutant, the Exon19 deletion activating mutant and the T790M resistancemutant). Such compounds and salts thereof may be useful in the treatmentor prevention of a number of different cancers. The invention alsorelates to pharmaceutical compositions comprising said compounds andsalts thereof, especially useful polymorphic forms of these compoundsand salts, intermediates useful in the manufacture of said compounds andto methods of treatment of diseases mediated by various different formsof EGFR using said compounds and salts thereof.

EGFR is a transmembrane protein tyrosine kinase member of the erbBreceptor family. Upon binding of a growth factor ligand such asepidermal growth factor (EGF), the receptor can homo-dimerise withanother EGFR molecule or hetero-dimerise with another family member suchas erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4).

Homo- and/or hetero-dimerisation of erbB receptors results in thephosphorylation of key tyrosine residues in the intracellular domain andleads to the stimulation of numerous intracellular signal transductionpathways involved in cell proliferation and survival. Deregulation oferbB family signalling promotes proliferation, invasion, metastasis,angiogenesis, and tumour cell survival and has been described in manyhuman cancers, including those of the lung, head and neck and breast.

The erbB family therefore represents a rational target for anticancerdrug development and a number of agents targeting EGFR or erbB2 are nowclinically available, including gefitinib (IRESSA™), erlotinib(TARCEVA™) and lapatinib (TYKERB™, TYVERB™). Detailed reviews of erbBreceptor signalling and its involvement in tumourigenesis are providedin New England Journal of Medicine (2008) Vol. 358, 1160-74 andBiochemical and Biophysical Research Communications (2004) Vol. 319,1-11.

In 2004 it was reported (Science [2004] Vol. 304, 1497-500 and NewEngland Journal of Medicine [2004] Vol. 350, 2129-39) that activatingmutations in EGFR correlated with response to gefitinib therapy innon-small-cell lung cancer (NSCLC). The most common EGFR activatingmutations, L858R and delE746_A750, result in an increase in affinity forsmall molecule tyrosine kinase inhibitors such as gefitinib anderlotinib and a decrease in affinity for adenosine triphosphate (ATP)relative to wild type (WT) EGFR. Ultimately, acquired resistance totherapy with gefitinib or erlotinib arises, for example by mutation ofthe gatekeeper residue T790M, which is reportedly detected in 50% ofclinically resistant patients. This mutation is not believed to hinderthe binding of gefitinib or erlotinib to EGFR sterically, merely toalter the affinity to ATP to levels comparable to WT EGFR.

In view of the importance of this mutation in resistance to existingtherapies targeting EGFR, we believe that agents which can inhibit EGFRharbouring the gatekeeper mutation may be especially useful in thetreatment of cancer.

There remains a need for compounds that may exhibit favourable potencyprofiles against WT EGFR versus activating mutant forms of EGFR (forexample the L858R EGFR mutant, or the delE746_A750 mutant or the Exon19deletion EGFR mutant) and/or resistant mutant forms of EGFR (for exampleT790M EGFR mutant), and/or selectivity over other enzyme receptors whichmay make the compounds especially promosing for development astherapeutic agents. In this regard, there remains a need for compoundsthat show a higher inhibition of certain activating or resistance mutantforms of EGFR while at the same time showing relatively low inhibitionof WT EGFR. Such compounds may be expected to be more suitable astherapeutic agents, particularly for the treatment of cancer, due toreduction of toxicology associated with WT EGFR inhibition. Suchtoxicologies are known to manifest themselves in man as skin rashesand/or diarrhea. The applicants have surprisingly found that one or more2-(2,4,5-substituted-anilino)pyrimidine compounds have high potencyagainst several mutant forms of EGFR, while at the same showingrelatively low inhibition of WT EGFR.

The compound(s) of the invention may also exhibit advantageous physicalproperties (for example, higher aqueous solubility, higher permeability,and/or lower plasma protein binding) and/or favourable toxicity profiles(for example a decreased hERG blocking liability) and/or favourablemetabolic profiles in comparison with other known EGFR/EGFR-mutantinhibitors. Therefore, such compound(s) may be especially useful in thetreatment of disease states in which EGFR and/or activating mutations ofEGFR and/or resistance mutations of EGFR are implicated, for example inthe treatment of cancer.

In the first aspect of the invention there is provided a compound ofFormula (I):

wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (35)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        [2-(methylamino)ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl        [2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), as shownabove, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), as shownabove, wherein:

-   -   G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and        pyrazolo[1,5-a]-pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

A suitable pharmaceutically acceptable salt of a compound of Formula (I)is, for example, an acid-addition salt. For example, an acid additionsalt may be formed using an inorganic or organic acid. An acid additionsalt may be formed using an inorganic acid selected from hydrochloricacid, hydrobromic acid, sulphuric acid and phosphoric acid. An acidaddition salt may be formed using an organic acid selected fromtrifluoroacetic acid, citric acid, maleic acid, oxalic acid, aceticacid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaricacid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonicacid and p-toluenesulfonic acid.

In one embodiment there is provided the mesylate salt ofN-(2-{2-dimethylamino-ethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)-prop-2-enamide.

It will be understood that the compound of Formula (I), andpharmaceutically acceptable salts thereof, may exist in solvated formsand unsolvated forms. For example a solvated form may be a hydratedform. It is to be understood that the present invention encompasses allsuch solvated and unsolvated forms.

The compound of Formula (I) may be administered in the form of a prodrugwhich is broken down in the human or animal body to give a compound ofthe Formula (I). Examples of prodrugs include in-vivo hydrolysableesters of a compound of the Formula (I). In-vivo hydrolysable esters maybe formed by esterification of the hydroxyl group in the compound ofFormula (I). Various forms of prodrugs are known in the art. Forexamples of such prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

One aspect of the invention provides compounds of Formula (I) thatinhibit one or more activating or resistance mutations of EGFR, forexample the L858R activating mutant, the Exon19 deletion EGFR activatingmutant and the T790M resistance mutant. Advantageously such compoundsmay be useful for the treatment of cancer in a patient who hasdeveloped, or may be at risk of developing a level of resistance to anexisting therapy based on an EGFR inhibitor.

In one aspect of the invention there are provided compounds of Formula(I) that show a higher inhibition of activating or resistance mutantforms of EGFR than of WT EGFR. Such compounds may be expected to be moresuitable as therapeutic agents, particularly for the treatment ofcancer, due to reduction of toxicology associated with WT EGFRinhibition. Such toxicologies are known to manifest themselves in man asskin rashes and/or diarrhea.

In one embodiment there is provided a compound of Formula (I), as shownhereinbefore, wherein:

-   -   G is selected from 1H-indol-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)-ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl;        4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-amino-propanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is selected from 1H-indol-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        3-(dimethylamino)-azetidin-1-yl,        [2-(dimethylamino)ethyl](methyl)amino,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl and        4-methylpiperizin-1-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is 1-methyl-1H-indol-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydro-pyridin-4-yl and        4-[(2S)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is 1-methyl-1H-indol-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        3-(dimethylamino)-azetidin-1-yl,        [2-(dimethylamino)ethyl](methyl)amino and        4-methylpiperizin-1-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydro-pyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)-ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from [2-(dimethylamino)-ethyl](methyl)amino,        (3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        (3R)-3-(dimethylamino)pyrrolidin-1-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl,        3-(dimethylamino)azetidin-1-yl,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl;        or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of Formula (I), asshown hereinabove, wherein:

-   -   G is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is hydrogen;    -   R² is methoxy; and    -   R³ is selected from [2-(dimethylamino)-ethyl](methyl)amino,        (3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        (3R)-3-(dimethylamino)pyrrolidin-1-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl,        3-(dimethylamino)azetidin-1-yl,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl;        or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I), as shownabove, wherein:

-   -   G is 1H-indol-3-yl or 1-methyl-1H-indol-3-yl;    -   R¹ is hydrogen;    -   R² is methoxy; and    -   R³ is [2-(dimethylamino)ethyl]-(methyl)amino or        [2-(methylamino)ethyl](methyl)amino;        or a pharmaceutically acceptable salt thereof.

Some values of variable groups are as follows. Such values may be usedin combination with any of the definitions, claims, aspects orembodiments defined herein to provide further embodiments of theinvention:

-   -   G is 1H-indol-3-yl.    -   G is 1-methyl-1H-indol-3-yl.    -   G is pyrazolo[1,5-a]pyridin-3-yl.    -   G is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl.    -   R¹ is hydrogen.    -   R¹ is chloro.    -   R¹ is methyl.    -   R¹ is cyano.    -   R² is methoxy.    -   R³ is (3R)-3-(dimethylamino)pyrrolidin-1-yl.    -   R³ is (3S)-3-(dimethylamino)pyrrolidin-1-yl.    -   R³ is 3-(dimethylamino)azetidin-1-yl.    -   R³ is [2-(dimethylamino)ethyl](methyl)amino.    -   R³ is [2-(methylamino)ethyl](methyl)amino.    -   R³ is 5-methyl-2,5-diazaspiro[3.4]oct-2-yl.    -   R³ is (3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl.    -   R³ is 1-methyl-1,2,3,6-tetrahydropyridin-4-yl.    -   R³ is 4-methylpiperizin-1-yl.    -   R³ is 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl.    -   R³ is methyl[2-(4-methylpiperazin-1-yl)ethyl]amino.    -   R³ is methyl[2-(morpholin-4-yl)ethyl]amino.    -   R³ is 1-amino-1,2,3,6-tetrahydropyridin-4-yl.    -   R³ is 4-[(2S)-2-aminopropanoyl]piperazin-1-yl.

In a further embodiment of the invention, relating to any claim orembodiment of Formula (I) described or derivable herein, or apharmaceutically acceptable salt thereof, there is provided such a claimor embodiment where one of the Example compounds of this application isdisclaimed. For the avoidance of doubt, the Example compounds are thoselisted as Example 1, Example 2, etc, in the experimental sectionhereinafter.

Therefore, for example, in one embodiment there is provided a compoundof Formula (I), as shown above, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        [2-(methylamino)ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl        [2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof,        wherein the compound of Formula (I) is other than        N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

Therefore, in one embodiment there is provided a compound of Formula(I), as shown above, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof,        wherein the compound of Formula (I) is other than        N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

Therefore, in a further embodiment there is provided a compound ofFormula (I), as shown above, wherein:

-   -   G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and        pyrazolo[1,5-a]-pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-aminopropanoyl]piperazin-1-yl;        or a pharmaceutically acceptable salt thereof,        wherein the compound of Formula (I) is other than        N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

In further embodiments of the invention there is provided any one of theExample compounds, (as named hereinafter in the Experimental section, inits free base form).

In further embodiments of the invention there is provided any one of theExample compounds (as named hereinafter in the Experimental section inits free base form), or a pharmaceutically acceptable salt thereof.

Therefore, examples of just some of the above-mentioned embodiments aregiven below:

In one embodiment there is providedN-(5-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}-4-methoxyphenyl)prop-2-enamide.

In one embodiment there is providedN-(5-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethyl-aminoethyl-methylamino}-4-methoxyphenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)-prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(5-{[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)-prop-2-enamide.

In one embodiment there is providedN-(5-{[5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(5-{[5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide.

In one embodiment there is providedN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

In one embodiment there is providedN-(5-{[5-cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(5-{[5-cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop-2-enamide.

In one embodiment there is providedN-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[2-dimethylaminoethyl-methylamino]-4-methoxyphenyl}prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[2-dimethylaminoethyl-methylamino]-4-methoxyphenyl}prop-2-enamide.

In one embodiment there is providedN-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4-methoxyphenyl}prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4-methoxyphenyl}prop-2-enamide.

In one embodiment there is providedN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

In one embodiment there is providedN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-{2-[2-dimethylaminoethyl-methylamino]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide.

In one embodiment there is providedN-{2-[2-dimethylaminoethyl-methylamino]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(2-[2-dimethylaminoethyl-methylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide.

In one embodiment there is providedN-(2-[2-dimethylaminoethyl-methylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-[methyl-(2-methylaminoethyl)amino]phenyl)prop-2-enamide,or a pharmaceutically acceptable salt thereof.

In one embodiment there is providedN-(4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-[methyl-(2-methylaminoethyl)amino]phenyl)prop-2-enamide.

The compounds of Formula (I) may be prepared by reaction of a compoundof Formula (II):

or a salt thereof, (wherein G, R¹, R² and R³ are as defined herein) withan activated acrylic acid derivative (e.g. acrolyl chloride or acorresponding activated ester), in a solvent such as CH₂Cl₂,tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide. Theintermediate compounds of Formula (II) therefore provide a furtheraspect of the present invention.

Therefore, in a further aspect of the invention there is provided acompound of Formula (II), (as shown above) wherein:

-   -   G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and        pyrazolo[1,5-a]-pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(25)-2-(tert-butoxycarbonyl)amino-propanoyl]piperazin-1-yl;        or a salt thereof.

In one embodiment there is provided a compound of Formula (II), (asshown above) wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-(tert-butoxycarbonyl)amino-propanoyl]piperazin-1-yl;        or a salt thereof.

In a further embodiment there is provided a compound of Formula (II),(as shown above) wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        [2-(methylamino)ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl        [2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-aminopropanoyl]piperazin-1-yl;        or a salt thereof.

In further embodiments of the invention there is provided any one of theIntermediate compounds, (as named hereinafter in the Experimentalsection, in its free base form).

In further embodiments of the invention there is provided any one of theIntermediate compounds (as named hereinafter in the Experimental sectionin its free base form), or a pharmaceutically acceptable salt thereof.

Therefore, examples of just some of the above-mentioned embodiments aregiven below:

In one embodiment there is provided Intermediate 100, or a salt thereof.

Therefore, in this case, there is providedN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine,or a salt thereof.

In one embodiment there is providedN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine.

In one embodiment there is provided Intermediate 168, or a salt thereof.

Therefore, in this case there is providedN¹-(2-dimethylaminoethyl)-N⁴-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N¹-methylbenzene-1,2,4-triamineor a salt thereof.

In one embodiment there is providedN¹-(2-dimethylaminoethyl)-N⁴-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N¹-methylbenzene-1,2,4-triamine.

The amine compounds of Formula (II) may be prepared by reduction of thecorresponding nitro compounds. Where G is indol-3-yl then the nitrogenatom of the indole group may be protected by a suitable nitrogenprotecting group, for example a phenylsulfonyl protecting group. Forexamples of protecting groups, including protecting groups suitable forprotecting nitrogen atoms (as well as means of formation and eventualdeprotection), see T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Second Edition, John Wiley & Sons, New York, 1991.

These further intermediates provide a further aspect of the invention.

Therefore, an a further aspect of the invention there is provided acompound of Formula (III):

wherein:

-   -   G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl an        1-(N-protecting group)-indol-3-yl and        pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethylamino)-pyrrolidin-1-yl;        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-(tert-butoxycarbonyl)amino-propanoyl]piperazin-1-yl;        or a salt thereof.

In one embodiment of this aspect of the invention there is provided acompound of Formula (III), as shown above, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl an 1-(N-protecting group)-indol-3-yl and        pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethylamino)-pyrrolidin-1-yl;        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-(tert-butoxycarbonyl)amino-propanoyl]piperazin-1-yl;        or a salt thereof.

In a further embodiment of this aspect of the invention there isprovided a compound of Formula (III), as shown above, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl an 1-(N-protecting group)-indol-3-yl and        pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano;    -   R² is methoxy; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        [2-(methylamino)ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4] oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxo ethyl]piperazin-1-yl, methyl        [2-(4-methylpiperazin-1-yl)ethyl]amino, methyl        [2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-aminopropanoyl]piperazin-1-yl;        or a salt thereof.

One example of the ‘N-protecting group’ within a ‘1-(N-protectinggroup)-indol-3-yl’ is a phenylsulfonyl group.

In one embodiment there is provided Intermediate 101, or a salt thereof.

Therefore, in this case, there is providedN′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine,or a salt thereof.

In one embodiment there is providedN′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine.

In one embodiment there is provided Intermediate 169, or a salt thereof.

Therefore, in this case there is providedN′-(2-dimethylaminoethyl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine,or a salt thereof.

In one embodiment there is providedN′-(2-dimethylaminoethyl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine.

In one embodiment there is provided Intermediate 175, or a salt thereof.Therefore, in this case there is providedN⁴-(2-dimethylaminoethyl)-2-methoxy-N⁴-methyl-N¹-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-diamine,or a salt thereof.

In one embodiment there is providedN⁴-(2-dimethylaminoethyl)-2-methoxy-N⁴-methyl-N¹-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-diamine.

Some compounds of Formula (III) have the R³ group attached to the phenylring of Formula (III) via a nitrogen atom of the R³ group: Thesecompounds may be prepared by is reacting the appropriate amine with theappropriate fluoro compound. Such intermediates provide a further aspectof the invention.

Therefore in a further aspect of the invention there is provided acompound of Formula (IV):

wherein:

-   -   G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and        pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano; and    -   R² is methoxy;        or a salt thereof.

In one embodiment of this aspect of the invention there is provided acompound of Formula (IV), as shown above, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano; and    -   R² is methoxy;        or a salt thereof.

In one embodiment there is provided Intermediate 68, or a salt thereof.

Therefore, in this case there is providedN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine,or a salt thereof.

In one embodiment there is providedN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine.

In one embodiment there is provided Intermediate 129, or a salt thereof.

Therefore in this case there is providedN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine,or a salt thereof.

In one embodiment there is providedN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine.

In one embodiment there is provided Intermediate 176, or a salt thereof.

Therefore, in this case there is providedN-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)-pyrimidin-2-amine,or a salt thereof.

In one embodiment there is providedN-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)-pyrimidin-2-amine.

Some compounds of Formula (III) have the R³ group attached to the phenylring of Formula (III) via a carbon atom of the R³ group. These compoundsmay be prepared by reacting the appropriate organoboron compound (forexample a boronate ester compound) with the appropriate aryl bromide oraryl chloride compound. For example, the organoboron compound may be(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-R³. These intermediatesprovide a further aspect of the present invention.

Therefore, in a further aspect of the invention there is provided acompound of Formula (V):

wherein:

-   -   X is bromo or chloro;    -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, chloro, methyl and cyano; and    -   R² is methoxy;        or a salt thereof.

In one embodiment for the compound of Formula (V), X is bromo.

In one embodiment for the compound of Formula (V), X is chloro.

In one embodiment there is provided Intermediate 145.

Therefore, in this case there is providedN-(4-bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine,or a salt thereof.

In one embodiment there is providedN-(4-bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine.

Advantageously, compounds of the present invention may be prepared byreaction of a compound of Formula (II) with 3-chloropropanoyl chloridein the presence of a base (for example an alkali metal carbonate base,for example potassium carbonate, in a suitable solvent, for exampleacetone. An intermediate compound of Formula (VI) is thus formed, whichmay be isolated as a solid (in free base form or as a salt), or it maybe kept in solution and treated with a base (for example an alkali metalhydroxide, for example NaOH), to convert the compound of Formula (VI) tothe corresponding compound of Formula (I). Therefore, compounds ofFormula (VI), and salts thereof are useful chemical intermediates in theformation of the compounds of Formula (I). Therefore, in a furtheraspect of the invention there is provided a compound of Formula (VI):

or a salt thereof, wherein G, R¹, R² and R³ are as defined herein.

In one embodiment there is provided the compound of Formula (VI), asshown above, or a salt thereof, wherein:

-   -   G is selected from        4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl,        1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        [2-(methylamino)ethyl](methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-aminopropanoyl]piperazin-1-yl.

In a further embodiment, there is provided the compound of Formula (VI),as shown above, or a salt thereof, wherein:

-   -   G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and        pyrazolo[1,5-a]-pyridin-3-yl;    -   R¹ is selected from hydrogen, fluoro, chloro, methyl and cyano;    -   R² is selected from methoxy and methyl; and    -   R³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl,        (3S)-3-(dimethyl-amino)pyrrolidin-1-yl,        3-(dimethylamino)azetidin-1-yl,        [2-(dimethylamino)ethyl]-(methyl)amino,        5-methyl-2,5-diazaspiro[3.4]oct-2-yl,        (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl,        1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl,        4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl,        methyl[2-(4-methylpiperazin-1-yl)ethyl]amino,        methyl[2-(morpholin-4-yl)ethyl]amino,        1-amino-1,2,3,6-tetrahydropyridin-4-yl and        4-[(2S)-2-aminopropanoyl]piperazin-1-yl.

In a further embodiment there is provided Intermediate 174, or a saltthereof.

Therefore, in this case, there is provided3-chloro-N-[2-[2-dimethylaminoethyl-(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-propanamide,or a salt thereof.

In one embodiment there is provided3-chloro-N-[2-[2-dimethylaminoethyl-(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-propanamide.

Other intermediates are be useful in the preparation of some compoundsof Formula (I). Therefore, for example, in one embodiment there isprovided Intermediate 170, or a salt thereof. In a further embodimentthere is provided Intermediate 171 or a salt thereof. In a furtherembodiment there is provided Intermediate 172, or a salt thereof. In oneembodiment there is provided Intermediate 144, or a salt thereof.

According to a further aspect of the invention there is provided apharmaceutical composition, which comprises the compound of the Formula(I), or a pharmaceutically acceptable salt thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The compound of Formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg/m² bodyarea of the animal, i.e. approximately 0.1-100 mg/kg, and this normallyprovides a therapeutically-effective dose. A unit dose form such as atablet or capsule will usually contain, for example 1-250 mg of activeingredient. The daily dose will necessarily be varied depending upon thehost treated, the particular route of administration, and the severityof the illness being treated. Accordingly the practitioner who istreating any particular patient may determine the optimum dosage.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

As used herein, the term “treatment” is intended to have its normaleveryday meaning of dealing with a disease in order to entirely orpartially relieve one, some or all is of its symptoms, or to correct orcompensate for the underlying pathology.

As used herein, the term “prophylaxis” is intended to have its normaleveryday meaning and includes primary prophylaxis to prevent thedevelopment of the disease and secondary prophylaxis whereby the diseasehas already developed and the patient is temporarily or permanentlyprotected against exacerbation or worsening of the disease or thedevelopment of new symptoms associated with the disease.

As a result of its inhibitory activity against the L858R EGFR mutant,the T790M EGFR mutant and the Exon19 deletion activating mutant, thecompound of Formula (I), and pharmaceutically acceptable salts thereof,are expected to be useful in the treatment of diseases or medicalconditions mediated alone or in part by EGFR mutant activity, forexample cancer. The types of cancers which may be susceptible totreatment using the compound of Formula (I), or pharmaceuticallyacceptable salts thereof, include, but are not limited to, ovariancancer, cervical cancer, colorectal cancer, breast cancer, pancreaticcancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia,lymphoma, non-Hodgkins lymphoma, gastric cancer, lung cancer,hepatocellular cancer, gastric cancer, gastrointestinal stromal tumour(GIST), thyroid cancer, bile duct cancer, endometrial cancer, renalcancer, anaplastic large cell lymphoma, acute myeloid leukaemia (AML),multiple myeloma, melanoma and mesothelioma.

It is envisaged that for the methods of treatment of cancer mentionedherein, the compound of Formula (I) will be administered to a mammal,more particularly a human being. Similarly, for the uses of the compoundof Formula (I) for the treatment of cancer mentioned herein, it isenvisaged that the compound of Formula (I) will be administered to amammal, more particularly a human being.

According to a another aspect of the invention, there is thereforeprovided the compound of Formula (I) as defined hereinbefore, or apharmaceutically acceptable salt thereof, for use as a medicament.

According to a further aspect of the invention, there is provided thecompound of Formula (I) as defined hereinbefore, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a disease mediatedthrough L858R EGFR mutant and/or T790M EGFR and/or the Exon19 deletionactivating mutant. In one embodiment of the invention, said diseasemediated through L858R EGFR mutant and/or T790M EGFR mutant and/or theExon19 deletion activating mutant is cancer.

According to a further aspect of the invention, there is provided theuse of the compound of Formula (I) as defined hereinbefore, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of a disease mediated through L858R EGFRmutant and/or T790M EGFR mutant and/or the Exon19 deletion activatingmutant. In one embodiment of the invention, said disease mediatedthrough L858R EGFR mutant and/or T790M EGFR mutant and/or the Exon19deletion activating mutant is cancer.

According to a further aspect of the invention, there is provided theuse of the compound of Formula (I) as defined hereinbefore, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer.

According to a further aspect of the invention, there is provided amethod of using a compound of Formula (I) as defined hereinbefore, or apharmaceutically acceptable salt thereof, for the treatment of cancer.

According to this aspect of the invention there is provided a method forproducing an anti-cancer effect in a warm-blooded animal, such as man,in need of such treatment, which comprises administering to said animalan effective amount of the compound of Formula (I), or apharmaceutically acceptable salt thereof, as defined herein.

According to a further aspect of the invention, there is provided amethod of treating a human suffering from a disease in which inhibitionof L858R EGFR mutant and/or T790M EGFR mutant and/or the Exon19 deletionactivating mutant is beneficial, comprising the steps of administeringto a person in need thereof of a therapeutically effective amount of thecompound of Formula (I) as defined hereinbefore, or a pharmaceuticallyacceptable salt thereof. In one embodiment of the invention, the diseasein which inhibition of L858R EGFR mutant and/or T790M EGFR mutant and/orthe Exon19 deletion activating mutant is beneficial is cancer.

In any of the aspects or embodiments mentioned herein where cancer ismentioned in a general sense, said cancer may be selected from ovariancancer, cervical cancer, colorectal cancer, breast cancer, pancreaticcancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia,lymphoma, non-Hodgkins lymphoma, gastric cancer, lung cancer,hepatocellular cancer, gastric cancer, gastrointestinal stromal tumour(GIST), thyroid cancer, bile duct cancer, endometrial cancer, renalcancer, anaplastic large cell lymphoma, acute myeloid leukaemia (AML),multiple myeloma, melanoma and mesothelioma.

In any aspect or embodiment of the invention where cancer is mentionedin a general sense the following embodiments may apply:

In one embodiment the cancer is ovarian cancer.

In one embodiment the cancer is cervical cancer.

In one embodiment the cancer is colorectal cancer.

In one embodiment the cancer is breast cancer.

In one embodiment the cancer is pancreatic cancer.

In one embodiment the cancer is glioma.

In one embodiment the cancer is glioblastoma.

In one embodiment the cancer is melanoma.

In one embodiment the cancer is prostate cancer.

In one embodiment the cancer is leukaemia.

In one embodiment the cancer is lymphoma.

In one embodiment the cancer is non-Hodgkins lymphoma.

In one embodiment the cancer is gastric cancer.

In one embodiment the cancer is lung cancer.

In one embodiment the cancer is non-small cell lung cancer.

In one embodiment the cancer is hepatocellular cancer.

In one embodiment the cancer is gastric cancer.

In one embodiment the cancer is gastrointestinal stromal tumour (GIST).

In one embodiment the cancer is thyroid cancer.

In one embodiment the cancer is bile duct cancer.

In one embodiment the cancer is endometrial cancer.

In one embodiment the cancer is renal cancer.

In one embodiment the cancer is anaplastic large cell lymphoma.

In one embodiment the cancer is acute myeloid leukaemia (AML).

In one embodiment the cancer is multiple myeloma.

In one embodiment the cancer is melanoma.

In one embodiment the cancer is mesothelioma.

The anti-cancer treatment described hereinbefore may be applied as asole therapy is or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy orimmunotherapy. Such chemotherapy could be administered concurrently,simultaneously, sequentially or separately to treatment with thecompound of the invention and may include one or more of the followingcategories of anti-tumour agents:—

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;

(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline[AZD0530 (saracatinib); WO01/94341],N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) andbosutinib (SKI-606), and metalloproteinase inhibitors like marimastat,inhibitors of urokinase plasminogen activator receptor function orantibodies to Heparanase];

(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB 1 is antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in WO97/22596, WO97/30035, WO97/32856 and WO98/13354 andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in WO99/02166, WO00/40529, WO00/41669, WO01/92224, WO02/04434and WO02/08213;

(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;

(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines, approaches using anti-idiotypicantibodies, approaches to decrease the function of immune suppressivecells such as regulatory T cells, myeloid-derived suppressor cells orIDO (indoleamine 2,3,-deoxygenase)-expressing dendritic cells, andapproaches using cancer vaccines consisting of proteins or peptidesderived from tumour-associated antigens such as NY-ESO-1, MAGE-3, WT1 orHer2/neu.

Therefore, in a further aspect of the invention there is provided apharmaceutical product comprising the compound of Formula (I) as definedhereinbefore, and an additional anti-tumour substance, as definedhereinbefore, for the conjoint treatment of cancer.

In such an aspect of the invention there is provided a pharmaceuticalproduct comprising the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, as defined herein, and an additionalanti-tumour substance, as defined hereinbefore, for the conjointtreatment of cancer.

Herein, where the term “conjoint treatment” is used in reference to acombination treatment, it is to be understood that this may refer tosimultaneous, separate or sequential administration. References to“conjoint administration” should be constued similarly. In one aspect ofthe invention “conjoint treatment” refers to simultaneousadministration. In another aspect of the invention “conjoint treatment”refers to separate administration. In a further aspect of the invention“conjoint treatment” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the benefit of the effectarising from use of the combination. Therefore, in one embodimentsequential treatment involves administration of each component of thecombination within a period of 11 days. In another embodiment thisperiod is 10 days. In another embodiment this period is 9 days. Inanother embodiment this period is 8 days. In another embodiment thisperiod is 7 days. In another embodiment this period is within 6 days. Inanother embodiment this period is within 5 days. In another embodimentthis period is within 4 days. In another embodiment this period iswithin 3 days. In another embodiment this period is within 2 days. Inanother embodiment this period is within 24 hours. In another embodimentthis period is within 12 hours.

Therefore, in one embodiment of the invention there is provided the useof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, as defined herein, and an additional anti-tumour substance forthe conjoint treatment of cancer.

In one embodiment of the invention there is provided the use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as defined herein, and an additional anti-tumour substance for thesimultaneous, separate or sequential treatment of cancer.

In one embodiment there is provided a method of producing an anti-cancereffect in a warm-blooded animal, such as man, who is in need of suchtreatment, which comprises administering to said mammal a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, andconjointly administering an additional anti-tumour substance to saidmammal, wherein the amounts of the compound of Formula (I), orpharmaceutically acceptable salt thereof, and the additional anti-tumoursubstance are jointly effective in producing an anti-cancer effect.

In one embodiment there is provided a method of producing an anti-cancereffect in a warm-blooded animal, such as man, who is in need of suchtreatment, which comprises administering to said mammal a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, andsimultaneously, separately or sequentially administering an additionalanti-tumour substance to said mammal, wherein the amounts of thecompound of Formula (I), or pharmaceutically acceptable salt thereof,and the additional anti-tumour substance are jointly effective inproducing an anti-cancer effect.

In the formulation of drug compositions, it is important for the drugsubstance to be in a form in which it can be conveniently handled andprocessed. This is of importance, not only from the point of view ofobtaining a commercially viable manufacturing process, but also from thepoint of view of subsequent manufacture of pharmaceutical formulations(e.g. oral dosage forms such as tablets) comprising the active compound.

The different physical properties of the crystalline forms with respectto each other and with respect to the non-crystalline state mayinfluence markedly the chemical and pharmaceutical processing of acompound, particularly when the compound is prepared or used on anindustrial scale.

Further, in the manufacture of oral drug compositions, it is importantthat a reliable and reproducible plasma concentration profile of drug isprovided following administration to a patient. Inter-patientvariability in the absorption profile of a drug within the stomach,intestine or bloodstream can have an effect on drug safety and efficacy.

Chemical stability, solid state stability and “shelf life” of the activeingredients are also very important factors. The drug substance, andcompositions containing it, should be capable of being effectivelystored over appreciable periods of time, without exhibiting asignificant change in the active component's physico-chemicalcharacteristics (e.g. its chemical composition, density, hygroscopicityand solubility).

Moreover, it is also important to be able to provide drug in a formwhich is as chemically pure as possible.

Amorphous materials may present problems in this regard. For example,such materials are typically difficult to handle and to formulate,provide for unreliable solubility, and are often found to be unstableand chemically impure.

The skilled person will appreciate that, if a drug can be readilyobtained in a stable crystalline form, the above problems may be solved.

Thus, in the manufacture of commercially viable, and pharmaceuticallyacceptable, drug compositions, it is important, wherever possible, toprovide drug in a crystalline, and stable, form.

It is to be noted, however, that this goal is not always achievable.Indeed, typically, it is not possible to predict, from molecularstructure alone, what the crystallisation behaviour of a compound,either as such or in the form of a salt, will be. This can only bedetermined empirically.

In a further aspect of the invention, certain compounds and saltsthereof may be prepared in crystalline forms. These crystalline formsmay be characterised as being a particular polymorphic form. When it isstated that the present invention relates to a crystalline form, thedegree of crystallinity is conveniently greater than about 60%, moreconveniently greater than about 80%, preferably greater than about 90%and more preferably greater than about 95%. Most preferably the degreeof crystallinity is greater than about 98%.

The specific solid forms described herein provide X-ray powderdiffraction patterns substantially the same as the X-ray powderdiffraction patterns shown in the Figures and have the various 2-thetavalues as shown in the Tables included herein. It will be understoodthat the 2-theta values of a X-ray powder diffraction pattern may varyslightly from one machine to another or from one sample to another, andso the values quoted are not to be construed as absolute.

It is known that an X-ray powder diffraction pattern may be obtainedwhich has one or more measurement errors depending on measurementconditions (such as equipment or machine used). In particular, it isgenerally known that intensities in an X-ray powder diffraction patternmay fluctuate depending on measurement conditions. Therefore it shouldbe understood that the solid forms of the present invention are notlimited to the crystals that provide X-ray powder diffraction patternsthat are identical to the X-ray powder diffraction pattern shown in theFigures, and any crystals providing X-ray powder diffraction patternssubstantially the same as those shown in the Figures fall within thescope of the present invention. A person skilled in the art of X-raypowder diffraction is able to judge the substantial identity of X-raypowder diffraction patterns.

Persons skilled in the art of X-ray powder diffraction will realise thatthe relative intensity of peaks can be affected by, for example, grainsabove 30 μm in size and non-unitary aspect ratios, which may affectanalysis of samples. The skilled person will also realise that theposition of reflections can be affected by the precise height at whichthe sample sits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence the diffraction pattern data presented are not to betaken as absolute values. (Jenkins, R & Snyder, R. L. ‘Introduction toX-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C. W. (1948),Chemical is Crystallography, Clarendon Press, London; Klug, H. P. &Alexander, L. E. (1974), X-Ray Diffraction Procedures).

Generally, a measurement error of a diffraction angle in an X-ray powderdiffractogram is approximately plus or minus 0.2° 2-theta, and suchdegree of a measurement error should be taken into account whenconsidering the X-ray powder diffraction pattern in the Figures and whenreading data contained in the Tables included herein. Furthermore, itshould be understood that intensities might fluctuate depending onexperimental conditions and sample preparation (preferred orientation).

In this specificationN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamideis referred to as “Compound X”. The initially produced Compound X wasfound to be an amorphous solid. Several useful crystalline polymorphicforms have subsequently been produced using the conditions describedhereinafter in the experimental section. In all of the embodimentsrelating to solid forms recited herein, the peaks of the X-raydiffraction patterns are measured using CuKa radiation.

Polymorphic Form A of Compound X

Therefore in a further aspect of the invention there is providedpolymorphic Form A of Compound X. This polymorphic form may becharacterised in that it provides at least one of the following 20values measured using CuKa radiation: 7.8 and 21.8.

Polymorphic Form A of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 1.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are 7.8 (100%), 21.8 (73.4%), 13.3 (59.4%),6.6 (49.5%), 23.9 (40.5%), 9.6 (38.1%), 14.5 (35.3%), 15.6 (33.2%), 22.7(31.2%) and 19.1 (29.8%).

According to the present invention there is provided the polymorphicForm A of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=7.8°.

According to the present invention there is provided the polymorphicForm A of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=21.8°.

According to the present invention there is provided the polymorphicForm A of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=7.8° and 21.8°.

According to the present invention there is provided the polymorphicForm A of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=7.8, 21.8, 13.3, 6.6, 23.9, 9.6, 14.5,15.6, 22.7 and 19.1°.

According to the present invention there is provided polymorphic Form Aof Compound X which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 1.

According to the present invention there is provided polymorphic Form Aof Compound X, which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=7.8° plus or minus 0.2° 2-theta.

According to the present invention there is provided a polymorphic FormA of Compound X, which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=21.8° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm A of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at 2-theta=7.8° and 21.8° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided a polymorphic FormA of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=7.8, 21.8, 13.3, 6.6, 23.9, 9.6, 14.5, 15.6,22.7 and 19.1° wherein said values may be plus or minus 0.2° 2-theta.

Polymorphic Form B of Compound X

In a further aspect of the invention there is provided polymorphic FormB of Compound X. This polymorphic form may be characterised in that itprovides at least one of the following 2θ values measured using CuKaradiation: 9.3 and 23.4.

Polymorphic Form B of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 3.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (2θ), Intensity (%)] are 9.3 (100%), 23.4 (75.0%), 10.5 (63.6%),17.7 (54.3%), 21.0 (48.1%), 16.1 (46.4%), 26.1 (44.2%), 18.6 (41.8%),26.7 (32.2%) and 20.6 (30.9%).

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=9.3°.

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=23.4°.

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=9.3° and 23.4°.

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=9.3, 23.4, 10.5, 17.7, 21.0, 16.1, 26.1,18.6, 26.7 and 20.6°.

According to the present invention there is provided polymorphic Form Bof Compound X which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 3.

According to the present invention there is provided polymorphic Form Bof Compound X, which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=9.3° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=23.4° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at 2-theta=9.3° and 23.4° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm B of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=9.3, 23.4, 10.5, 17.7, 21.0, 16.1, 26.1, 18.6,26.7 and 20.6° wherein said values may be plus or minus 0.2° 2-theta.

Polymorphic Form C of Compound X

In a further aspect of the invention there is provided polymorphic FormC of Compound X. This polymorphic form may be characterised in that itprovides at least one of the following 2θ values measured using CuKaradiation: 6.0 and 11.3.

Polymorphic Form C of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 5.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (2θ), Intensity (%)] are 6.0 (100%), 11.3 (58.2%), 7.5 (40.5%),10.3 (21.9%), 12.0 (20.1%), 24.9 (19.4%), 13.0 (16.9%), 14.5 (13.5%),16.5 (13.5%) and 18.3 (11.8%).

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=6.0°.

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=11.3°.

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=6.0° and 11.3°.

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=6.0, 11.3, 7.5, 10.3, 12.0, 24.9, 13.0,14.5, 16.5, and 18.3°.

According to the present invention there is provided polymorphic Form Cof Compound X which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 5.

According to the present invention there is provided polymorphic Form Cof Compound X, which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=6.0° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=11.3° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withat least two specific is peaks at 2-theta=6.0° and 11.3° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm C of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=6.0, 11.3, 7.5, 10.3, 12.0, 24.9, 13.0, 14.5,16.5, and 18.3° wherein said values may be plus or minus 0.2° 2-theta.

Polymorphic Form D of Compound X

In a further aspect of the invention there is provided polymorphic FormD of Compound X which is believed to be a monohydrate crystalline form.This polymorphic form may be characterised in that it provides at leastone of the following 2θ values measured using CuKa radiation: 9.3 and10.5.

Polymorphic Form D of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 7.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are 9.3 (100%), 10.5 (90.6%), 16.1 (75.8%),26.1 (75.2%), 21.0 (70.9%), 20.6 (56.9%), 16.8 (56.5%), 17.7 (53.3%),14.7 (41.3%) and 9.7 (38.3%).

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=9.3°.

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=10.5°.

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=9.3° and 10.5°.

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=9.3, 10.5, 16.1, 26.1, 21.0, 20.6, 16.8,17.7, 14.7, and 9.7°.

According to the present invention there is provided polymorphic Form Dof Compound X which has an X-ray powder diffraction patternsubstantially the same as the is X-ray powder diffraction pattern shownin FIG. 7.

According to the present invention there is provided polymorphic Form Dof Compound X, which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=9.3° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=10.5° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at 2-theta=9.3° and 10.5° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm D of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=9.3, 10.5, 16.1, 26.1, 21.0, 20.6, 16.8, 17.7,14.7, and 9.7° wherein said values may be plus or minus 0.2° 2-theta.

Polymorphic Form E of Compound X

In a further aspect of the invention there is provided polymorphic FormE of Compound X which is believed to be a 1.25 stoichiometry hydratedform of Compound X. This polymorphic form may be characterised in thatit provides at least one of the following 2θ values measured using CuKaradiation: 9.2 and 22.9.

Polymorphic Form E of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 10.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are: 9.2 (100%), 22.9 (84.0%), 14.6(80.3%), 12.7 (77.8%), 16.5 (66.4%), 26.9 (60.3%), 9.7 (95.6%), 14.0(52.3%), 10.4 (49.9%) and 19.5 (48.3%).

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=9.2°.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=22.9°.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=9.2° and 22.9°.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=9.2, 22.9, 14.6, 12.7, 16.5, 26.9, 9.7,14.0, 10.4 and 19.5°.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 10.

According to the present invention there is provided polymorphic Form Eof Compound X which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=9.2° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=22.9° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withat least two specific peaks at 2-theta=9.2° and 22.9° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm E of Compound X which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=9.2, 22.9, 14.6, 12.7, 16.5, 26.9, 9.7, 14.0,10.4, and 19.5° wherein said values may be plus or minus 0.2° 2-theta.

Polymorphic Form F of Compound X

In a further aspect of the invention there is provided polymorphic FormF of Compound X which is believed to be a 0.25 stoichiometry hydratedform of Compound X. This polymorphic form may be characterised in thatit provides at least one of the following 2θ values measured using CuKaradiation: 18.7 and 8.9.

Polymorphic Form F of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 13.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are: 18.7 (100%), 8.9 (87.7%), 15.1(80.3%), 25.4 (74.6%), 14.5 (72.3%), 22.9 (69.6%), 9.9 (51.1%), 28.2(42.0%), 8.2 (24.2%) and 11.9 (22.3%).

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=18.7°.

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=8.9°.

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=18.7° and 8.9°.

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=18.7, 8.9, 15.1, 25.4, 14.5, 22.9, 9.9,28.2, 8.2 and 11.9°.

According to the present invention there is provided polymorphic Form Fof Compound X which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 13.

According to the present invention there is provided polymorphic Form Fof Compound X, which has an X-ray powder diffraction pattern with atleast one specific peak at 2-theta=18.7° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=8.9° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at 2-theta=18.7° and 8.9° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm F of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=18.7, 8.9, 15.1, 25.4, 14.5, 22.9, 9.9, 28.2,8.2 and 11.9° wherein said values may be plus or minus 0.2° 2-theta.

Polymorphic Form K of Compound X

In a further aspect of the invention there is provided polymorphic FormK of Compound X. This polymorphic form may be characterised in that itprovides at least one of the following 2θ values measured using CuKaradiation: 8.4 and 9.7.

Polymorphic Form F of Compound X is characterised in providing an X-raypowder diffraction pattern, substantially as shown in FIG. 16.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are: 8.4 (100%), 9.7 (37.7%), 12.2 (32.4%),15.1 (25.2%), 24.7 (20.7%), 9.0 (16.8%), 21.9 (13.9%), 19.5 (13.9%),24.2 (13.8%) and 18.3 (11.8%).

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=8.4°.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at about 2-theta=9.7°.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at about 2-theta=8.4° and 9.7°.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at about 2-theta=8.4, 9.7, 12.2, 15.1, 24.7, 9.0, 21.9,19.5, 24.2 and 18.3°.

According to the present invention there is provided the polymorphicForm K of Compound X which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 16.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=8.4° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=9.7° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withat least two specific peaks at 2-theta=8.4° and 9.7° wherein said valuesmay be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm K of Compound X, which has an X-ray powder diffraction pattern withspecific peaks at 2-theta=8.4, 9.7, 12.2, 15.1, 24.7, 9.0, 21.9, 19.5,24.2 and 18.3° wherein said values may be plus or minus 0.2° 2-theta.

In this specification the mesylate salt ofN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamideis referred to as “Mesylate Salt Y”.

Polymorphic Form A of Mesylate Salt Y

In a further aspect of the invention there is provided polymorphic FormA of Mesylate Salt Y. This polymorphic form may be characterised in thatit provides at least one of the following 2θ values measured using CuKaradiation: 5.6 and 6.5.

Polymorphic Form A of Mesylate Salt Y is characterised in providing anX-ray powder diffraction pattern, substantially as shown in FIG. 18.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are: 5.6 (100%), 6.5 (66.7%), 10.2 (97.2%),21.0 (96.2%), 13.5 (91.7%), 22.7 (89.6%), 19.3 (80.6%), 27.3 (75.7%),15.7 (71.2%) and 19.9 (66.7%).

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least one specific peak at about 2-theta=5.6°.

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least one specific peak at about 2-theta=6.5°.

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least two specific peaks at about 2-theta=5.6° and 6.5°.

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith specific peaks at about 2-theta=5.6, 6.5, 10.2, 21.0, 13.5, 22.7,19.3, 27.3, 15.7 and 19.9°.

According to the present invention there is provided polymorphic Form Aof Mesylate Salt Y which has an X-ray powder diffraction patternsubstantially the same as is the X-ray powder diffraction pattern shownin FIG. 18.

According to the present invention there is provided polymorphic Form Aof Mesylate Salt Y, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=5.6° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least one specific peak at 2-theta=6.5° plus or minus 0.2°2-theta.

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least two specific peaks at 2-theta=5.6° and 6.5° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm A of Mesylate Salt Y, which has an X-ray powder diffraction patternwith specific peaks at 2-theta=5.6, 6.5, 10.2, 21.0, 13.5, 22.7, 19.3,27.3, 15.7 and 19.9° wherein said values may be plus or minus 0.2°2-theta.

Polymorphic Form B of Mesylate Salt Y

In a further aspect of the invention there is provided polymorphic FormB of Mesylate Salt Y. This polymorphic form may be characterised in thatit provides at least one of the following 2θ values measured using CuKaradiation: 7.2 and 8.6.

Polymorphic Form A of Mesylate Salt Y is characterised in providing anX-ray powder diffraction pattern, substantially as shown in FIG. 20.

Ten X-Ray powder diffraction peaks for this polymorphic form [Angle2-theta (20), Intensity (%)] are: 7.2 (50.2%), 8.6 (55.2%), 15.3 (100%),10.4 (92.6%), 25.7 (74.0%), 26.1 (63.9%), 16.4 (55.2%), 9.5 (47.5%),22.1 (46.9%) and 18.8 (47.7%).

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least one specific peak at about 2-theta=7.2°.

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least one specific peak at about 2-theta=8.6°.

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least two specific peaks at about 2-theta=7.2° and 8.6°.

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith specific peaks at about 2-theta=7.2, 8.6, 15.3, 10.4, 25.7, 26.1,16.4, 9.5, 22.1 and 18.8°.

According to the present invention there is provided polymorphic Form Bof Mesylate Salt Y which has an X-ray powder diffraction patternsubstantially the same as the X-ray powder diffraction pattern shown inFIG. 20.

According to the present invention there is provided polymorphic Form Bof Mesylate Salt Y, which has an X-ray powder diffraction pattern withat least one specific peak at 2-theta=7.2° plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least one specific peak at 2-theta=8.6° plus or minus 0.2°2-theta.

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith at least two specific peaks at 2-theta=7.2° and 8.6° wherein saidvalues may be plus or minus 0.2° 2-theta.

According to the present invention there is provided the polymorphicForm B of Mesylate Salt Y, which has an X-ray powder diffraction patternwith specific peaks at 2-theta=7.2, 8.6, 15.3, 10.4, 25.7, 26.1, 16.4,9.5, 22.1 and 18.8° wherein said values may be plus or minus 0.2°2-theta.

LIST OF FIGURES

All figures relate to solid forms of the compound:N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide(“Compound X”) or its mesylate salt where indicated (“Mesylate Salt Y”).

FIG. 1: X-Ray Powder Diffraction Pattern—Form A

FIG. 2: DSC Thermogram—Form A

FIG. 3: X-Ray Powder Diffraction Pattern—Form B

FIG. 4: DSC Thermogram—Form B

FIG. 5: X-Ray Powder Diffraction Pattern—Form C

FIG. 6: DSC Thermogram—Form C

FIG. 7: X-Ray Powder Diffraction Pattern—Form D (Monohydrate)

FIG. 8: DSC Thermogram—Form D Monohydrate

FIG. 9: TGA Thermogram—Form D Monohydrate

FIG. 10: X-Ray Powder Diffraction Pattern—Form E (Hydrated Form)

FIG. 11: DSC Thermogram—Form E (Hydrated Form)

FIG. 12: TGA Thermogram—Form E (Hydrated form)

FIG. 13: X-Ray Powder Diffraction—Form F (Hydrated Form)

FIG. 14: DSC Thermogram—Form F (Hydrated Form)

FIG. 15: TGA Thermogram—Form F (Hydrated form)

FIG. 16: X-Ray Powder Diffraction Pattern—Form K

FIG. 17: DSC Thermogram—Form K

FIG. 18: X-Ray Powder Diffraction Pattern—Mesylate salt Form A

FIG. 19: DSC Thermogram—Mesylate salt Form A

FIG. 20: X-Ray Powder Diffraction Pattern—Mesylate salt Form B

FIG. 21: DSC Thermogram—Mesylate salt Form B

CHEMICAL SYNTHESIS AND BIOLOGICAL ASSAY PROCEDURES

The following abbreviations may be used: Abbreviations:THF=tetrahydrofuran; DIPEA=diisopropylethylamine; sat.=saturated aqueoussolution; FCC=flash column chromatography using silica;TFA=trifluoroacetic acid; r.t.=room temperature;DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide;DMA=N,N-dimethylacetamide; EtOAc=ethyl acetate; h.=hour(s); Proton NMR:(¹H NMR) was determined using deuterated dimethylsulfoxide at 400 or 500MHz at around 20-30° C., unless otherwise stated. Standard NMRabbreviations are used, (s=singlet; d=doublet; dd=double of doublets;t=triplet; q=quartet; p=pentet; m=multiplet; br=broad; etc.). Where ironwas mentioned as a reagent, it was iron powder, 325 mesh and hydrogenreduced. Quoted assay values (μM) for a given Example are IC₅₀ values.X-Ray Powder Diffraction (XRPD) was carried out using a Bruker D4instrument. The X-ray powder diffractogram was determined by mounting asample of the crystalline material on a Bruker single silicon crystal(SSC) wafer mount and spreading out the sample into a thin layer withthe aid of a microscope slide. The sample was spun at 30 revolutions perminute (to improve counting statistics) and irradiated with X-raysgenerated by a copper long-fine focus tube operated at 40 kV and 40 mAwith a wavelength of 1.5418 angstroms (CuKa radiation). The collimatedX-ray source was passed through an automatic variable divergence slitset at V20 and the reflected radiation directed through a 5.89 mmantiscatter slit and a 9.55 mm detector slit. The sample was exposed for0.03 seconds per 0.00570° 2-theta increment (continuous scan mode) overthe range 2 degrees to 40 degrees 2-theta in theta-theta mode. Therunning time was 3 minutes and 36 seconds. The instrument was equippedwith a Position sensitive detector (Lynxeye). Control and data capturewas by means of a Dell Optiplex 686 NT 4.0 Workstation operating withDiffrac+software. Differential Scanning Calorimetry (DSC) was carriedout using a “TA Instruments Q1000 differential scanning calorimeter.Typically less than 5 mg of material contained in a standard aluminiumpan fitted with a lid was heated over the temperature range 25° C. to300° C. at a constant heating rate of 10° C. per minute. A purge gasusing nitrogen was used—flow rate 50 mL per minute. Any crystal formthat provides a XRPD diffractogram or DSC thermogram substantiallyidentical to those disclosed herein fall within the scope of the presentinventions. One skilled in the art will have the ability to determinesubstantial identities of diffractograms and thermograms.

Assay 1: Exon19 Deletion EGFR (Activating Single Mutant) CellularPhosphorylation Assay

The human lung cell line PC9 (Exon 19 deletion EGFR) were obtained fromthe American type Culture Collection. PC9 were maintained in RPMI 1640,containing 10% fetal calf serum and 2 mM glutamine. Cells were grown ina humidified incubator at 37° C. with 5% CO₂. Assays to measure cellularphosphorylation of endogenous p-EGFR in cell lysates were carried outaccording to the protocol described in the R&D Systems DuoSet IC HumanPhospho-EGF R ELISA (R&D Systems catalogue number #DYC1095).

40 μL of cells were seeded (10000 cells/well) in growth medium inCorning black, clear-bottomed 384-well plates and incubated at 37° C.with 5% CO₂ overnight. Cells were acoustically dosed using an Echo 555,with compounds serially diluted in 100% DMSO. Plates were incubated fora further 2 h, then following aspiration of medium, 40 μL× lysis bufferwas added to each well. Greiner black high bind 384-well plates werecoated with capture antibody and then blocked with 3% BSA. Followingremoval of block, 15 μL of lysate were transferred to the Greiner blackhigh bind 384-well plates and incubated for 2 hours. Followingaspiration and washing of the plates with PBS, 20 μL of detectionantibody were added and incubated for 2 hours. Following aspiration andwashing of the plates with PBS, 20 μL of QuantaBlu fluorogenicperoxidase substrate (Thermo Fisher Scientific catalogue number 15169)were added and incubated for 1 hour. 20 μL QuantaBlu stop solution wereadded to plates and fluorescence read on an Envision plate reader usingExcitation 352 nm wavelength and emission 460 nm wavelength. The dataobtained with each compound was exported into a suitable softwarepackage (such as Origin) to perform curve fitting analysis. From thisdata an IC₅₀ value was determined by calculation of the concentration ofcompound that is required to give a 50% effect.

Assay 2: L858R/T790M EGFR (Double Mutant) Cellular Phosphorylation Assay

The human lung cell lines NCI-H1975 were obtained from the American typeCulture Collection. NCI-H1975 were maintained in RPMI 1640, containing10% fetal calf serum and 2 mM glutamine. Cells were grown in ahumidified incubator at 37° C. with 5% CO₂. Assays to measure cellularphosphorylation of endogenous p-EGFR in cell lysates were carried outaccording to the protocol described in the R&D Systems DuoSet IC HumanPhospho-EGF R ELISA (R&D Systems catalogue number #DYC1095).

40 μL of cells were seeded (10000 cells/well) in growth medium inCorning black, clear-bottomed 384-well plates and incubated at 37° C.with 5% CO₂ overnight. Cells were acoustically dosed using an Echo 555,with compounds serially diluted in 100% DMSO. Plates were incubated fora further 2 h and following aspiration of medium, 40 μL 1× lysis bufferwas added to each well. Greiner black high bind 384-well plates werecoated with capture antibody and then blocked with 3% BSA. Followingremoval of block, 15 μL of lysate were transferred to the Greiner blackhigh bind 384-well plates and incubated for 2 hours. Followingaspiration and washing of the plates with PBS, 20 μL of detectionantibody were added and incubated for 2 hours. Following aspiration andwashing of the plates with PBS, 20 μL of QuantaBlu fluorogenicperoxidase substrate (Thermo Fisher Scientific catalogue number 15169)were added and incubated for 1 hour. 20 μL QuantaBlu stop solution wereadded to plates and fluorescence read on an Envision plate reader usingExcitation 352 nm wavelength and emission 460 nm wavelength. The dataobtained with each compound was exported into a suitable softwarepackage (such as Origin) to perform curve fitting analysis. From thisdata an IC₅₀ value was determined by calculation of the concentration ofcompound that is required to give a 50% effect.

Assay 3: Wild-Type EGFR Cellular Phosphorylation Assay

The human colon cell line LoVo were obtained from the American typeCulture Collection. LoVo were maintained in RPMI 1640, containing 3%stripped fetal calf serum and 2 mM glutamine. Cells were grown in ahumidified incubator at 37° C. with 5% CO₂. Assays to measure cellularphosphorylation of endogenous p-EGFR in cell lysates were carried outaccording to the protocol described in the R&D Systems DuoSet IC HumanPhospho-EGF R ELISA (R&D Systems catalogue number #DYC1095).

40 μL of cells were seeded (15000 cells/well) in growth medium inCorning black, clear-bottomed 384-well plates and incubated at 37° C.with 5% CO₂ overnight. Cells were acoustically dosed using an Echo 555,with compounds serially diluted in 100% DMSO. Plates were incubated fora further 2 h then stimulated with 100 ng/ml for 10 minutes andfollowing aspiration of medium, 40 μL 1× lysis buffer was added to eachwell. Greiner black high bind 384-well plates were coated with captureantibody and then blocked with 3% BSA. Following removal of block, 15 μLof lysate were transferred to the Greiner black high bind 384-wellplates and incubated for 2 hours. Following aspiration and washing ofthe plates with PBS, 20 μL of detection antibody were added andincubated for 2 hours. Following aspiration and washing of the plateswith PBS, 20 μL of QuantaBlu fluorogenic peroxidase substrate (ThermoFisher Scientific catalogue number 15169) were added and incubated for 1hour. 20 μL QuantaBlu stop solution were added to plates andfluorescence read on an Envision plate reader using Excitation 352 nmwavelength and emission 460 nm wavelength. The data obtained with eachcompound was exported into a suitable software package (such as Origin)to perform curve fitting analysis. From this data an IC₅₀ value wasdetermined by calculation of the concentration of compound that isrequired to give a 50% effect.

The assay data (μM) for the Examples of this application are shown inthe table below. While assay data is stated with a certain number ofsignificant figures, this should not be taken as a representation thatthe data has been determined to be accurate to that number ofsignificant figures.

Ex. No. Assay 1 Assay 2 Assay 3  1 0.007614 0.004956 0.4744  2 0.0012910.001504 0.04122  3 0.01054 0.01549 0.5222  4 0.01273 0.0016 0.5099  50.02059 0.003402 0.8225  6 0.002183 0.0006695 0.1959  7 0.0032620.0006825 0.1606  8 0.02239 0.005481 1.17  9 0.009959 0.002818 0.8744 100.07377 0.03998 8.427 11 0.02854 0.01871 1.599 12 0.03613 0.005821 1.39313 0.1388 0.01926 11.91 14 0.05328 0.01912 12.48 15 0.01399 0.055241.067 16 0.1437 0.07052 >18.92 17 0.02344 0.005644 0.772 18 0.066440.03138 2.696 19 0.002149 0.001463 0.07081 20 0.007487 0.005276 0.192921 0.002948 0.002339 0.1283 22 0.002137 0.001524 0.07336 23 0.016940.01759 3.018 24 0.001327 0.0008856 0.03567 25 0.0005811 0.0002380.01092 26 0.002289 0.001925 0.05831 27 0.00561 0.01142 0.3177 280.01292 0.01144 0.4938 28A 0.01975 0.01271 1.443 29 0.001228 0.00088460.04652 30 0.07375 0.05211 1.613 31 0.03746 0.00734 2.506 32 0.1380.02378 10.53 33 0.8916 1.158 11.86 34 0.009044 0.003767 0.1526 350.008571 0.006772 0.2623 36 0.04329 0.03272 1.051 37 0.002112 0.0018140.04859 38 0.005092 0.004405 0.5384 39 0.002336 0.001005 0.2484 400.0124 0.01477 >30 41 0.02863 0.0295 1.841 42 0.005192 0.005161 0.454243 0.01817 0.01055 1.34 44 0.03329 0.0256 3.64 45 0.1102 0.041 7.396 460.1289 0.09293 7.091 47 0.1939 0.1192 15.45 48 0.03988 0.03098 1.579 490.0742 0.05097 3.093 50 0.1145 0.1297 7.626 51 0.01296 0.007713 0.462252 0.02603 0.01501 1.4 53 0.03537 0.02824 2.638 54 0.003217 0.0028030.1832 55 0.006433 0.002863 0.5066 56 0.04433 0.02922 3.504 57 0.0064550.01452 0.08931 58 0.007085 0.01683 0.1786 59 0.002266 0.003021 0.0281660 0.0146 0.04886 0.6241

Example 1N-{4-Methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

Acryloyl chloride (0.331 mL, 1M in THF, 0.33 mmol) was added dropwise toa solution of6-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-1-[5-methyl-4-(pyrazolo[1,5-a]-pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 1, 146 mg, 0.33 mmol) and DIPEA (0.086 mL, 0.50 mmol) inTHF (4 mL) at −10° C. over a period of 1 minute under N₂. The resultingmixture was stirred at 0° C. for 15 minutes and then concentrated invacuo. The residue was dissolved in CH₂Cl₂ (5 mL) plus a little CH₃OH.This solution was then washed with sat. NaHCO₃ (2 mL), dried (MgSO₄) andthen concentrated in vacuo. Purification by FCC, eluting with 5-25%CH₃OH in CH₂Cl₂ and concentration of appropriate fractions in vacuoprovided material that was dissolved in CH₂Cl₂:7N methanolic ammonia100:8 (1 mL) and filtered through a 1 g silica plug. Concentration ofthe resulting solution provided the title compound (70 mg, 38%) as apale orange foam; ¹H NMR: 2.27 (3H, s), 2.37 (2H, m), 2.42 (3H, s),2.53-2.57 (2H, m), 2.97 (2H, m), 3.87 (3H, d), 5.66 (2H, d), 6.14 (1H,d), 6.39 (1H, d), 6.86 (1H, s), 7.07 (1H, t), 7.42 (1H, m), 7.98 (1H,s), 8.17 (1H, s), 8.32 (1H, s), 8.48 (1H, d), 8.58 (1H, s), 8.81 (1H,d), 9.29 (1H, s); m/z: ES⁺ MH⁺ 496.

Example 2N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]phenyl)prop-2-enamide

Acryloyl chloride (0.217 mL, 1M in THF, 0.22 mmol) was added dropwise toa slurry ofN′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine(Intermediate 7, 100 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.33 mmol) inTHF (3 mL) at −5° C. over a period of 1 minute under N₂. The resultingmixture was stirred at 0° C. for 15 minutes and then concentrated invacuo. The residue was dissolved in CH₂Cl₂ (5 mL) plus a few drops ofCH₃OH, and washed with sat. NaHCO₃ (2 mL). The organic solution was thendried (MgSO₄) and loaded onto silica in vacuo. Purification by FCC,eluting with 5-25% CH₃OH in CH₂Cl₂ and concentration of appropriatefractions in vacuo provided a residue that was washed with CH₃OH (0.3mL) and dried in air to give the title compound (37 mg, 31%) as a beigecrystalline solid. ¹H NMR: 2.28 (3H, s), 2.38 (2H, m), 2.55 (2H, m),2.98 (2H, d), 3.85 (3H, s), 5.6-5.72 (2H, m), 6.15 (1H, m), 6.41 (1H,m), 6.88 (1H, s), 7.10 (1H, t), 7.18 (1H, t), 7.47 (1H, d), 7.98 (1H,s), 8.33 (1H, s), 8.36 (1H, d), 8.42 (1H, s), 8.49 (1H, s), 9.29 (1H,s), 11.86 (1H, s); m/z: ES⁺ MH⁺ 515.

Example 3N-(5-{[4-(1H-Indol-3-yl)-5-methylpyrimidin-2-yl]amino}-4-methoxy-2-[4-methylpiperazin-1-yl]phenyl)prop-2-enamide

Acryloyl chloride (0.025 mL, 0.30 mmol) was added dropwise toN′-[4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 12, 135 mg, 0.30 mmol) and DIPEA (0.090 mL, 0.33 mmol) inCH₂Cl₂ (10 mL) and DMF (2 mL) at 0° C. under N₂. The resultingsuspension was stirred at 0° C. for 2 h. then allowed to warm to r.t.The mixture was then diluted with water (15 mL) and extracted withCH₂Cl₂ (40 mL). The resulting organic solution was washed with sat.Na₂CO₃ (20 mL) and then sat. brine (20 mL). The solution was then dried(MgSO₄) and concentrated in vacuo. Purification by FCC, eluting with1-5% 7M methanolic ammonia in CH₂Cl₂ gave crude product. Furtherpurification by preparative HPLC (Waters SunFire column, 5μ it silica,19 mm diameter, 100 mm length), eluting with decreasingly polar mixturesof water (containing 0.1% formic acid) and CH₃CN, followed by HPLC(Waters XBridge Prep C18 OBD column, 5μ it silica, 19 mm diameter, 100mm length), eluting with decreasingly polar mixtures of water(containing 1% NH₃) and CH₃CN, gave the title compound (23 mg, 15%) as awhite solid; ¹H NMR: 2.26 (3H, s), 2.37 (3H, s), 2.48-2.57 (4H, m), 2.87(4H, t), 3.84 (3H, s), 5.70 (1H, d), 6.18 (1H, dd), 6.59 (1H, dd), 6.87(1H, s), 7.05 (1H, dd), 7.15 (1H, t), 7.44 (1H, d), 7.83 (1H, s), 7.98(1H, d), 8.22 (1H, s), 8.34 (1H, d), 8.49 (1H, s), 8.97 (1H, s), 11.68(1H, s); m/z: ES⁺ MH⁺ 498.60.

Example 4N-{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[(3R)-3-dimethylaminopyrrolidin-1-yl]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.042 mL, 0.51 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture ofN-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine(Intermediate 18, 245 mg, 0.51 mmol) and DIPEA (0.097 mL, 0.56 mmol) inCH₂Cl₂ (10 mL), which was cooled in an ice/water bath. The mixture wasstirred for 2 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave a foam after concentration in vacuo.This foam was triturated using CH₂Cl₂ and diethyl ether, and theresulting solid was collected by filtration and dried to give the titlecompound (157 mg, 58%) as a yellow solid; ¹H NMR: 1.68-1.83 (1H, m),2.05-2.16 (1H, m), 2.18 (6H, s), 2.64-2.76 (1H, m), 3.18-3.29 (3H, m),3.36-3.47 (1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H,dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H, t), 7.43 (1H, s), 8.28-8.46(2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z:ES⁺ MH⁺ 533.5.

Example 5N-[5-{5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.038 mL, 0.47 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred solution ofN-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-(3-dimethylamino-azetidin-1-yl)-6-methoxybenzene-1,3-diamine(Intermediate 24, 220 mg, 0.47 mmol) and DIPEA (0.090 mL, 0.52 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 3 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (221 mg, 90%) as ayellow solid; ¹H NMR: 2.09 (6H, s), 3.08 (1H, p), 3.55-3.62 (2H, m),3.76 (3H, s), 3.97 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.25 (1H, s),6.45 (1H, dd), 7.10 (1H, dd), 7.35 (1H, s), 7.39 (1H, dd), 8.25-8.40(1H, m), 8.35 (1H, s), 8.45 (1H, s), 8.81 (1H, d), 8.92 (1H, s), 9.24(1H, s); m/z: ES⁺ MH⁺ 519.56.

Example 6N-[5-{5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[2-dimethylaminoethyl-methylamino]-4-methoxyphenyl}prop-2-enamide

Acryloyl chloride (1.248 mL, 1M in THF, 1.25 mmol) was added dropwise toN⁴-[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]-N¹-[2-(dimethylamino)ethyl]-5-methoxy-N¹-methylbenzene-1,2,4-triamine(Intermediate 33, 530 mg, 1.13 mmol) and DIPEA (0.244 mL, 1.36 mmol) inTHF (20 mL), which was cooled to 0° C. The mixture was stirred at 0° C.for 2 h. The mixture was then concentrated in vacuo. The resultingresidue was dissolved in CH₂Cl₂ (100 mL), then washed sequentially withsat. NaHCO₃ (25 mL), water (25 mL), and sat. brine (25 mL). The organicsolution was concentrated in vacuo. Purification by FCC, eluting with0-20% 2M methanolic ammonia in CH₂Cl₂ and further purification by FCC,eluting with 0-20% CH₃OH in CH₂Cl₂ gave a brown gum. LCMS analysisindicated that impurities were still present. A further attempt atpurification was made by FCC, eluting with 0-20% CH₃OH in CH₂Cl₂.Appropriate fractions were concentrated to provide a brown gumcontaining the title compound. Attempts to make this gum into a solid bytrituration were unsuccessful. Lyophilisation from CH₃CN/water alsofailed but lyophilisation from CH₃OH/water gave a brown semi-solid.Trituration of the semi-solid with diethyl ether followed by evaporationof the ether gave the title compound (191 mg, 32%) as a pale yellow,free-flowing solid; ¹H NMR: (CDCl₃) 2.28 (6H, s), 2.32 (2H, t), 2.71(3H, s), 2.84-2.92 (2H, m), 3.87 (3H, s), 5.67 (1H, dd), 6.29 (1H, dd),6.37 (1H, dd), 6.80 (1H, s), 6.89 (1H, td), 7.23-7.33 (1H, m), 7.46 (1H,s), 8.45 (1H, s), 8.52 (1H, d), 8.56 (1H, d), 8.94 (1H, s), 9.39 (1H,s), 10.09 (1H, s); m/z: ES⁺ MH⁺ 521.29.

Example 7N-{2-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-5-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxyphenyl}prop-2-enamide

Acryloyl chloride (1M in THF, 0.225 mL, 0.22 mmol) in CH₂Cl₂ (1 mL) wasadded dropwise to a mixture of4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene-1,3-diamine(Intermediate 35, 105 mg, 0.21 mmol) and DIPEA (0.041 mL, 0.24 mmol) inCH₂Cl₂ (3 mL), which was cooled in an ice/water bath. The mixture wasstirred for 0.5 h, washed with brine and then concentrated in vacuo.Purification by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH₂Cl₂gave the title compound (60 mg, 52%) as a pale yellow solid; ¹H NMR:1.77-1.81 (1H, m), 1.95-2.16 (5H, m), 2.24-2.35 (1H, m), 2.38-2.48 (1H,m), 2.86-2.90 (1H, m), 3.18-3.22 (1H, m), 3.37-3.45 (1H, m), 3.76 (3H,s), 4.33-4.37 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.51 (1H, dd), 6.66(1H, s), 7.10 (1H, dt), 7.33-7.41 (1H, m), 7.65 (1H, s), 8.3-8.4 (2H,m), 8.56 (1H, s), 8.81 (1H, d), 8.94 (1H, s), 9.38 (1H, s); m/z: ES⁺,MH⁺ 545.57.

Example 8N-{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[5-methyl-2,5-diazaspiro[3.4]octan-2-yl]phenyl}prop-2-enamide

A solution of acryloyl chloride (5.71 mg, 0.06 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture ofN′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)benzene-1,3-diamine(Intermediate 45, 31 mg, 0.06 mmol) in CH₂Cl₂ (5 mL), which was cooledin an ice/water bath. The mixture was stirred for 3 h and then washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. Purification byFCC, eluting with 0-2% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (21 mg, 61%) as a yellow foam; ¹H NMR: 1.70 (2H, dd), 1.98-2.11(2H, m), 2.37 (3H, s), 2.62 (2H, t), 3.65 (2H, d), 3.76 (3H, s), 3.95(2H, d), 5.67 (1H, d), 6.09-6.27 (2H, m), 6.43 (1H, dd), 7.10 (1H, t),7.30 (1H, s), 7.34-7.45 (1H, m), 8.35 (2H, s), 8.44 (1H, s), 8.81 (1H,d), 8.92 (1H, s), 9.20 (1H, s); m/z: ES⁺ MH⁺ 545.5.

Example 9N-{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]phenyl}prop-2-enamide

A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture ofN′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine(Intermediate 55, 150 mg, 0.32 mmol) and DIPEA (0.062 mL, 0.36 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 3 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2.5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (120 mg, 72%) as ayellow foam; ¹H NMR: 2.28 (3H, s), 2.38 (2H, s), 2.54 (2H, t), 2.98 (2H,d), 3.81 (3H, s), 5.62-5.73 (2H, m), 6.14 (1H, dd), 6.43 (1H, dd), 6.88(1H, s), 7.12 (1H, dt), 7.39-7.47 (1H, m), 7.83 (1H, s), 8.41-8.50 (2H,m), 8.63 (1H, s), 8.85 (1H, d), 8.95 (1H, s), 9.36 (1H, s); m/z: ES⁺ MH⁺516.25.

Example 10N-{5-{5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino}-2-[4-(2-dimethylamino-2-oxoethyl)piperazin-1-yl]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.030 mL, 0.37 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred solution of2-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-N,N-dimethylacetamide(Intermediate 57, 0.19 g, 0.35 mmol) and DIPEA (0.067 mL, 0.39 mmol) inCH₂Cl₂ (5 mL). The mixture was stirred for 0.5 h, then diluted withCH₂Cl₂ (20 mL) and washed with sat. brine (2×25 mL). The organicsolution was dried (MgSO₄), and concentrated in vacuo. Purification byFCC, eluting with 5% CH₃OH in CH₂Cl₂ gave the title compound (0.157 g,75%) as a yellow solid; ¹H NMR: (CDCl₃) 2.76 (4H, s), 2.90-2.96 (4H, m),2.98 (3H, s), 3.12 (3H, s), 3.30 (2H, s), 3.87 (3H, s), 5.65-5.77 (1H,m), 6.18-6.37 (2H, m), 6.80 (1H, s), 6.90 (1H, t), 7.28 (1H, d), 7.42(1H, s), 8.44 (1H, s), 8.46-8.59 (3H, m), 8.93 (1H, s), 9.33 (1H, s);m/z: ES⁺ MH⁺ 590.52.

Example 11(S)—N-{2-[4-(2-Aminopropanoyl)piperazin-1-yl]-5-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (10.2 μL, 0.13 mmol) in CH₂Cl₂ (3 mL)was added dropwise to a stirred solution of (S)-tert-butylN-[1-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate(Intermediate 59, 65 mg) and DIPEA (0.75 mL) in CH₂Cl₂ (10 mL), whichwas cooled in an ice/water bath. The mixture was stirred for 0.75 h.then quenched with water (10 mL) and 2M Na₂CO₃ (5 mL). The phases wereseparated and the organic solution was dried (MgSO₄) and concentrated invacuo. The resulting residue was dissolved in CH₂Cl₂ (3 mL) and was thentreated with TFA (0.1 mL). After standing for 0.25 h a second portion ofTFA (0.2 mL) was added. After a further 0.25 h the solution wasconcentrated in vacuo and purified by preparative HPLC (Waters SunFirecolumn, 5μ silica, 19 mm diameter, 100 mm length), eluting withdecreasingly polar mixtures of water (containing 0.1% formic acid) andCH₃CN. Fractions containing the desired compound were concentrated invacuo to give the title compound (17 mg, 6% from5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine)as a white solid; ¹H NMR: 1.25 (3H, s), 2.83-2.96 (4H, m), 3.65-3.82(7H, m), 4.14-4.23 (1H, m), 5.73 (1H, d), 61.9 (1H, d), 6.64-6.70 (1H,m), 6.69 (1H, s), 7.08-7.12 (1H, m) 7.30-7.37 (1H, m), 8.20-8.28 (2H,m), 8.35-8.41 (2H, m), 8.68 (1H, s), 8.80-8.84 (1H, m), 8.95 (1H, s),9.11-9.15 (1H, m); m/z: ES⁺ MH⁺ 576.60.

Example 12N-{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[(3S)-3-dimethylaminopyrrolidin-1-yl]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.042 mL, 0.52 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture of(S)—N¹-[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]-4-[3-(dimethylamino)pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine(Intermediate 61, 250 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 3 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (194 mg, 70%) as ayellow solid; ¹H NMR: 1.69-1.83 (1H, m), 2.05-2.16 (1H, m), 2.19 (6H,s), 2.65-2.78 (1H, m), 3.18-3.29 (3H, m), 3.35-3.46 (1H, m), 3.77 (3H,s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H,t), 7.37 (1H, t), 7.43 (1H, s), 8.3-8.46 (2H, m), 8.55 (1H, s), 8.83(1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES⁺ MH⁺ 533.5.

Example 13N-{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[4-methylpiperazin-1-yl]phenyl}prop-2-enamide

A solution of acryloyl chloride (0.092 mL, 1.14 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture ofN′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 63, 480 mg, 1.03 mmol) and DIPEA (0.214 mL, 1.24 mmol) inCH₂Cl₂ (18 mL) at r.t. After 0.25 h, additional acrolyl chloride (15 mgin 0.15 mL CH₂Cl₂) was added. The mixture was stirred for 0.5 h and thenwashed with brine, dried (Na₂SO₄) and concentrated in vacuo.Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH₂Cl₂gave the title compound (390 mg, 73%) as a yellow solid, aftertrituration with CH₃OH; ¹H NMR: 2.27 (3H, s), 2.53-2.61 (4H, m),2.84-2.97 (4H, m), 3.77 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.61 (1H,dd), 6.89 (1H, s), 7.11 (1H, t), 7.3-7.42 (1H, m), 8.10 (1H, s),8.26-8.47 (2H, m), 8.70 (1H, s), 8.83 (1H, d), 8.96 (1H, s), 9.02 (1H,s); m/z: ES⁺ MH⁺ 519.

Example 14N-{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[4-methylpiperazin-1-yl]phenyl}prop-2-enamide

A solution of acryloyl chloride (0.017 mL, 0.21 mmol) in CH₂Cl₂ (0.6 mL)was added to a mixture of2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile(Intermediate 65, 87 mg, 0.19 mmol) and DIPEA (0.063 mL, 0.38 mmol) inCH₂Cl₂ (1.5 mL) at 0° C. The mixture was then stirred at 0° C. for 4 h.(during this time a further 0.5 eq acryloyl chloride was added). Themixture was then diluted with CH₂Cl₂, washed twice with sat. NaHCO₃,then with water, and then dried (MgSO₄). Purification by FCC, elutingwith 0-6% methanolic ammonia in CH₂Cl₂ gave the title compound (67 mg,69%) as a yellow solid; ¹H NMR: (102° C.) 2.30 (3H, s), 2.56-2.59 (4H,m), 2.93-2.96 (4H, m), 3.78 (3H, s), 5.67-5.7 (1H, m), 6.16 (1H, d),6.44-6.51 (1H, m), 6.95 (1H, s), 7.11 (1H, t), 7.35 (1H, t), 8.20 (1H,s), 8.32 (1H, d), 8.66 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.91 (1H,s), 8.96 (1H, br s); m/z: ES⁺ MH⁺ 510.5.

Example 15N-(5-{[4-(1H-Indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

To a stirred solution ofN′-[4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 66, 96 mg, 0.22 mmol) in CH₂Cl₂ (15 mL) at 2° C. was addedDIPEA (0.039 mL, 0.22 mmol) and acryloyl chloride (0.018 mL, 0.22 mmol).The resulting solution was stirred at 2° C. for 0.25 h, then allowed towarm to r.t. and stirred for a further 3.5 h. The mixture was thendiluted with CH₃OH (10 mL), loaded directly onto silica. Purification byFCC, eluting with 0-10% CH₃OH in CH₂Cl₂ (containing 1% concentratedammonia (aq) gave the an off-white solid which appeared to containDIPEA.HCl according to MNR analysis. The solid was then dissolved in a1:1 mixture of CH₂Cl₂/2-methyltetrahydrofuran (30 mL) and the resultingsolution was washed with NaOH solution (2M, 2×30 mL), water (2×30 mL)and then sat. brine (30 mL). The organic solution was dried (MgSO₄) andconcentrated in vacuo to give the title compound (2 mg, 2%) as a whitesolid after trituration with diethyl ether. The liquors from thetrituration were concentrated in vacuo to give a second sample of thetitle compound (10 mg, 9%) as a white solid; ¹H NMR: 2.27 (3H, s), 2.55(4H, s), 2.82-2.95 (4H, m), 3.84 (3H, d), 5.73 (1H, d), 6.24 (1H, dd),6.62 (1H, dd), 6.89 (1H, s), 7.07-7.21 (2H, m), 7.25 (1H, d), 7.46 (1H,d), 7.89 (1H, s), 8.29 (1H, d), 8.32 (1H, d), 8.42 (1H, s), 8.69 (1H,s), 9.01 (1H, s); m/z: ES⁺ MH⁺ 484.62.

Example 16N-[4-Methoxy-2-(4-methylpiperazin-1-yl)-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl]prop-2-enamide

(2,3,4,5,6-Pentafluorophenyl) prop-2-enoate (0.030 mL, 0.19 mmol) wasadded dropwise to a solution of4-methoxy-6-(4-methylpiperazin-1-yl)-N′(4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine(Intermediate 69, 67 mg, 0.16 mmol) in DMF (0.6 mL) at r.t. under N₂.The resulting solution was stirred at r.t. for 1.5 h and then dilutedwith CH₂Cl₂ (9 mL). This solution was added to 1.5 g flash silica whichwas wet with CH₂Cl₂ in a dry-loaded cartridge, and the crude product waseluted from the silica using CH₂Cl₂. Further purification by FCC,eluting with 2-7% of 2N methanolic ammonia in CH₂Cl₂ provided materialwhich was further purified by FCC, eluting with 5-20% CH₃OH in CH₂Cl₂.Appropriate fractions were concentrated in vacuo and triturationprovided a crystalline solid that was washed with THF (0.1 mL) to givethe title compound (23 mg, 28%) as a beige crystalline solid; ¹H NMR:2.33-2.43 (3H, m), 2.62-2.81 (4H, m), 2.94 (4H, s), 3.85 (3H, s), 5.72(1H, d), 6.18 (1H, m), 6.55-6.69 (1H, m), 6.89 (1H, s), 7.05 (1H, m),7.26 (1H, d), 7.35-7.43 (1H, m), 8.15 (1H, s), 8.34 (1H, d), 8.44 (1H,d), 8.49 (1H, s), 8.79 (1H, d), 8.80 (1H, s), 9.03 (1H, s); m/z: ES⁺ MH⁺485.

Example 17N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

Acryloyl chloride (0.621 mL, 1M in THF, 0.62 mmol) was added dropwise toN′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 74, 288 mg, 0.62 mmol) and DIPEA (0.119 mL, 0.68 mmol) inTHF (15 mL) at 0° C. under N₂. The resulting suspension was stirred at0° C. for 1 h, and then allowed to warm to r.t. The mixture was thendiluted with water (15 mL) and concentrated in vacuo. The resultingresidue was dissolved in a mixture of CH₂Cl₂ (20 mL) and CH₃OH (5 mL)and the resulting solution was washed with water and sat. brine. Theorganic solution was dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH₂Cl₂gave crude product as a pale brown dry film. This material was dissolvedin CH₂Cl₂ and a beige solid precipitated from the solution. The solutionwas diluted with diethyl ether and then mixture filtered. The collectedsolid was washed with further diethyl ether and dried to give the titlecompound (134 mg, 42%) as a beige solid; ¹H NMR: 2.27 (3H, s), 2.53-2.59(4H, m), 2.87-2.94 (4H, m), 3.79 (3H, s), 5.70 (1H, d), 6.17 (1H, dd),6.60 (1H, dd), 6.89 (1H, s), 7.01 (1H, t), 7.16 (1H, t), 7.45 (1H, d),8.20 (1H, s), 8.27 (1H, d), 8.35 (1H, s), 8.43 (1H, s), 8.49 (1H, d),8.96 (1H, s), 11.81 (1H, s); m/z: ES⁺ MH⁺ 518.51.

Example 18N-(4-Methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

Acryloyl chloride (0.358 mL, 1M in THF, 0.36 mmol) was added dropwise toa mixture of4-methoxy-N′-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 77, 164 mg, 0.36 mmol) and DIPEA (0.069 mL, 0.39 mmol) inTHF (15 mL) at 0° C. under N₂. The resulting suspension was stirred at0° C. for 1 h, then allowed to warm to r.t. The mixture was then dilutedwith water (15 mL) and concentrated in vacuo. The resulting material wasdissolved in a mixture of CH₂Cl₂ (20 mL) and CH₃OH (5 mL). The resultingsolution was washed with water, and sat. brine. The organic solution wasthen dried (MgSO₄) and concentrated in vacuo. Purification by FCC,eluting with 1-8% 7M methanolic ammonia in CH₂Cl₂ gave a pale yellow dryfilm after concentration of the appropriate fractions in vacuo. Thismaterial was dissolved in CH₂Cl₂ and the resulting solution was dilutedwith diethyl ether, which resulted in a beige solid precipitating fromthe solution. This solid was collected by filtration, washed withdiethyl ether and then dried to give the title compound (96 mg, 52%); ¹HNMR: 2.26 (3H, s), 2.37 (3H, s), 2.51 (4H, s), 2.87 (4H, s), 3.83 (3H,s), 3.89 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.60 (1H, dd), 6.86 (1H,s), 7.09 (1H, t), 7.22 (1H, t), 7.48 (1H, d), 7.87 (1H, s), 8.05 (1H,s), 8.21 (1H, s), 8.37 (1H, d), 8.46 (1H, s), 9.00 (1H, s); m/z: ES⁺ MH⁺512.46.

Example 19N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

Acryloyl chloride (0.026 mL, 1M in THF, 0.32 mmol) was added dropwise toa mixture ofN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine(Intermediate 81, 147 mg, 0.32 mmol) and DIPEA (0.061 mL, 0.35 mmol) inTHF (15 mL) at 0° C. under N₂. The resulting suspension was stirred at0° C. for 1 h then allowed to warm to r.t. The mixture was then dilutedwith water (15 mL) and concentrated in vacuo. The resulting material wasdissolved in a mixture of CH₂Cl₂ (20 mL) and CH₃OH (5 mL). The resultingsolution was washed with water and sat. brine, and was then dried(MgSO₄) and concentrated in vacuo. Purification by FCC, eluting with1-8% 7M methnaolic ammonia in CH₂Cl₂ gave a yellow dry film afterconcentrating the appropriate fractions in vacuo. This material wasdissolved in CH₂Cl₂ and the resulting solution was diluted with diethylether. This was concentrated in vacuo and dried to give the titlecompound (93 mg, 57%) as a beige solid; ¹H NMR: 2.21 (6H, s), 2.28-2.34(2H, m), 2.37 (3H, s), 2.73 (3H, s), 2.89 (2H, t), 3.81 (3H, s), 3.89(3H, s), 5.72 (1H, dd), 6.19 (1H, dd), 6.38 (1H, dd), 7.02 (1H, d), 7.06(1H, d), 7.18-7.23 (1H, m), 7.48 (1H, d), 7.91 (1H, s), 8.06 (1H, s),8.22 (1H, s), 8.36 (1H, d), 8.75 (1H, s), 10.11 (1H, s); m/z: ES⁺ MH⁺514.36.

Example 20N-(2-{(3R)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

Acryloyl chloride (0.043 mL, 1M in THF, 0.53 mmol) was added dropwise toa mixture of4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 83, 252 mg, 0.53 mmol) and DIPEA (0.103 mL, 0.59 mmol) inTHF (15 mL) at 0° C. under N₂. The resulting suspension was stirred at0° C. for 1 h, and then allowed to warm to r.t. The mixture was thendiluted with water (15 mL) and concentrated in vacuo. The resultingmaterial was dissolved in a mixture of CH₂Cl₂ (20 mL) and CH₃OH (5 mL).The resulting solution was washed with water and sat. brine. The aqueouswashes were re-extracted three times using CH₂Cl₂. The combined organicsolutions were dried (MgSO₄) and concentrated in vacuo. Purification byFCC, eluting with 1-8% CH₃OH in CH₂Cl₂ gave a yellow dry film afterconcentration of the appropriate fractions in vacuo. This material wasdissolved in CH₂Cl₂ and the resulting solution was diluted with diethylether. The resulting mixture was stirred for 30 minutes and thenconcentrated in vacuo to give the title compound (133 mg, 47%) as ayellow solid; ¹H NMR: 1.67-1.81 (1H, m), 2.09 (1H, s), 2.19 (6H, s),2.35 (3H, s), 2.72 (1H, s), 3.20 (3H, t), 3.30-3.43 (1H, m), 3.84 (3H,s), 3.89 (3H, s), 5.66 (1H, d), 6.16 (1H, d), 6.49 (1H, dd), 6.55 (1H,s), 7.12 (1H, t), 7.22 (1H, t), 7.48 (1H, d), 7.75 (1H, s), 7.92 (1H,s), 8.02 (1H, s), 8.18 (1H, s), 8.40 (1H, d), 9.32 (1H, s); m/z: ES⁺ MH⁺526.66.

Example 21N-(5-{[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}-4-methoxyphenyl)prop-2-enamide

Acryloyl chloride (0.459 mL, 1M in THF, 0.46 mmol) was added dropwise toa mixture ofN-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine(Intermediate 85, 226 mg, 0.46 mmol) and DIPEA (0.088 mL, 0.51 mmol) inTHF (15 mL) at 0° C. under N₂. The resulting suspension was stirred at0° C. for 1 h, then allowed to warm to r.t. The mixture was then dilutedwith water (15 mL) and concentrated in vacuo. The resulting material wasdissolved in a mixture of CH₂Cl₂ (20 mL) and CH₃OH (5 mL). The resultingsolution was washed with water and sat. brine. The organic solution wasdried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 1-8% 7M methanolic ammonia in CH₂Cl₂ gave a yellow dry film afterconcentration of appropriate fractions in vacuo. This material wasdissolved in CH₂Cl₂ and the resulting solution was diluted with diethylether. This resulted in a yellow gelatinous solid precipitating from thesolution. The mixture was concentrated in vacuo and dried to give thetitle compound (142 mg, 57%) as a yellow solid; ¹H NMR: 1.68-1.81 (1H,m), 2.04-2.14 (1H, m), 2.18 (6H, s), 2.64-2.75 (1H, m), 3.22 (3H, dd),3.32-3.44 (1H, m), 3.78 (3H, s), 3.90 (3H, s), 5.66 (1H, dd), 6.16 (1H,dd), 6.49 (1H, dd), 6.54 (1H, s), 7.08 (1H, t), 7.23 (1H, t), 7.49 (1H,d), 7.54 (1H, s), 8.29-8.39 (3H, m), 8.53 (1H, s), 9.35 (1H, s); m/z:ES⁺ MH⁺ 546.57.

Example 22N-(5-{[5-Cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}-4-methoxyphenyl)prop-2-enamide

Acryloyl chloride (0.373 mL, 1M in THF, 0.37 mmol) was added dropwise toa mixture of2-({5-amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile(Intermediate 89, 180 mg, 0.37 mmol) and DIPEA (0.072 mL, 0.41 mmol) inTHF (15 mL) at 0° C. under N₂. The resulting suspension was stirred at0° C. for 1 h, then allowed to warm to r.t. The mixture was diluted withwater (15 mL) and then concentrated in vacuo. The resulting material wasdissolved in a mixture of CH₂Cl₂ (20 mL) and CH₃OH (5 mL). The resultingsolution was washed with water and sat. brine. The organic solution wasdried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 1-8% 7M methanolic ammonia in CH₂Cl₂ gave a yellow dry film afterconcentration of the appropriate fractions in vacuo. This material wasdissolved in CH₂Cl₂ and the resulting solution was diluted with diethylether. A yellow gelatinous solid then precipitated from the solution.Concentration of the mixture in vacuo gave the title compound (91 mg,46%) as a yellow solid; ¹H NMR: (100° C.) 1.82 (1H, dq), 2.04-2.11 (1H,m), 2.22 (6H, d), 2.85 (1H, dd), 3.20-3.39 (4H, m), 3.79 (3H, s), 3.90(3H, s), 5.62 (1H, d), 6.16 (1H, dd), 6.45 (1H, dd), 6.62 (1H, s), 7.10(1H, t), 7.25 (1H, t), 7.49 (1H, d), 7.65 (1H, s), 8.26 (1H, d), 8.42(1H, s), 8.59 (1H, s), 8.72 (1H, s), 8.93 (1H, s); m/z: ES⁺ MH⁺ 537.61.

Example 23N-(5-{[5-Cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

A solution of acryloyl chloride (39 mg, 0.43 mmol) in CH₂Cl₂ (1 mL) wasadded dropwise to a stirred solution of2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile(Intermediate 90, 200 mg, 0.43 mmol) and DIPEA (0.081 mL, 0.47 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1.5 h and then diluted with CH₂Cl₂ (25 mL). This mixture wasthen washed with sat. NaHCO₃ (50 mL). The aqueous washes were furtherextracted with CH₂Cl₂ (2×25 mL). The combined organic solutions weredried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound togetherwith some residual starting material. Further purification by FCC,eluting with 0-5% CH₃OH in CH₂Cl₂ gave a residue after concentration ofthe appropriate fractions in vacuo. This residue was dissolved in asmall amount of CH₂Cl₂ and trituration with diethyl ether gave a solidthat was collected by filtration and dried in vacuo to give the titlecompound (106 mg, 48%) as a cream solid; ¹H NMR: 2.27 (3H, s), 2.57 (4H,br s), 2.92 (4H, br s), 3.74 (3H, s), 3.91 (3H, s), 5.70 (1H, d), 6.17(1H, d), 6.63 (1H, dd), 6.90 (1H, s), 7.01 (1H, br s), 7.25 (1H, s),7.52 (1H, d), 7.88 (1H, br s), 8.02 (1H, s), 8.48 (1H, s), 8.67 (1H, s),9.03 (1H, s), 9.40 (1H, s); m/z: ES⁺ MH⁺ 523.27.

Example 24N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.044 mL, 0.54 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture ofN-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine(Intermediate 93, 258 mg, 0.54 mmol) and DIPEA (0.103 mL, 0.59 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 3 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The resulting residue was suspended in CH₃OH andfiltered to give some of the title compound (67 mg). The filtrate wasthen concentrated in vacuo and purified by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂. Appropriate fractions were combined andconcentrated in vacuo to give a solid which was suspended in CH₃OH andcollected by filtration to give more of the title compound (64 mg). Thetwo batches of product were combined to give the title compound (131 mg,46%) as a yellow solid; ¹H NMR: 1.68-1.83 (1H, m), 2.04-2.16 (1H, m),2.18 (6H, s), 2.63-2.77 (1H, m), 3.15-3.29 (3H, m), 3.35-3.46 (1H, m),3.78 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s),7.04 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.53 (1H, s), 8.23-8.4 (3H,m), 8.48 (1H, d), 9.34 (1H, s), 11.84 (1H, s); m/z: ES⁺ MH⁺ 532.5.

Example 25N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethyl-aminoethyl-methylamino}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.027 mL, 0.33 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture ofN⁴-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine(Intermediate 95, 155 mg, 0.33 mmol) and DIPEA (0.063 mL, 0.37 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (120 mg, 69%) as awhite solid after trituration with diethyl ether; ¹H NMR: 2.22 (6H, s),2.34 (2H, br t), 2.75 (3H, s), 2.91 (2H, br t), 3.76 (3H, s), 5.73 (1H,dd), 6.19 (1H, dd), 6.39 (1H, dd), 6.96 (1H, t), 7.05 (1H, s), 7.14 (1H,t), 7.44 (1H, d), 8.26 (1H, d), 8.35 (1H, s), 8.48 (1H, s), 8.50 (1H,d), 8.54 (1H, s), 10.10 (1H, s), 11.85 (1H, s); m/z: ES⁺ MH⁺ 520.6.

Example 26N-(5-{[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH₂Cl₂ (1 mL)was added to a mixture ofN⁴-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N¹-(2-dimethylamino-ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine(Intermediate 97, 130 mg, 0.27 mmol) and DIPEA (0.090 mL, 0.54 mmol) inCH₂Cl₂ (2 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 h(during this time a further 0.2 eq acryloyl chloride was added). Themixture was then diluted with CH₂Cl₂, washed twice with sat. NaHCO₃ andthen with water, dried (MgSO₄), and concentrated in vacuo. Purificationby FCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ gave the titlecompound (111 mg, 77%) as a yellow solid; ¹H NMR: (CDCl₃) 2.26 (6H, s),2.23-2.33 (2H, m), 2.70 (3H, s), 2.86-2.89 (2H, m), 3.88 (3H, s), 3.91(3H, s), 5.67 (1H, d), 6.25-6.44 (2H, m), 6.79 (1H, s), 7.20-7.37 (3H,m), 7.57 (1H, s), 8.36-8.45 (3H, m), 9.54 (1H, s), 10.11 (1H, s); m/z:ES⁺ MH⁺ 534, 536.

Example 27N-(5-{[5-Cyano-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise toa fine slurry of2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile(Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) inTHF (2 mL) at −10° C. over a period of 2 minutes under N₂. The mixturewas then stirred at 0° C. for 10 minutes then allowed to warm to r.t.over 20 minutes. The mixture was then cooled again to −10° C. andfurther acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was addeddropwise. The mixture was stirred at 0° C. for a further 10 minutes,then allowed to warm to r.t. over 20 minutes. The mixture was thenconcentrated in vacuo and the resulting reside was dissolved in CH₂Cl₂(2 mL). This solution was washed with sat. NaHCO₃ (1 mL), dried (MgSO₄)and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7Nmethanolic ammonia in CH₂Cl₂ gave a residue that was washed with CH₃OH(0.1 mL) and dried in air to give the title compound (11 mg, 20%) as acream crystalline solid; ¹H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93(4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91(2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67(1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES⁺ MH⁺ 509.

Example 28N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred mixture ofN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine(Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1.5 h and then diluted with CH₂Cl₂ (25 mL) and washed withsat.NaHCO₃ (50 mL). The aqueous washes were extracted with CH₂Cl₂ (2×25mL). The combined organic solutions were dried (MgSO₄) and concentratedin vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammoniain CH₂Cl₂ gave the title compound (75 mg, 39%) as a cream solid aftertrituration with diethyl ether; ¹H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72(3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27(1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m),7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s),9.14 (1H, s), 10.22 (1H, s); m/z: ES⁺ MH⁺ 500.42.

Example 28 Alternative Synthesis 1N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

To a stirred solution of3-chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide(Intermediate 174, 31.5 g, 58.76 mmol) in acetonitrile (310 mL) wasadded triethylamine (17.84 g, 176.28 mmol) at r.t. The resulting mixturewas heated to 80° C. for 6 h then cooled to r.t. Water (130 mL) was thenadded and the mixture stirred for 12 h. The mixture was then filtered,washed with a mixture of water and acetonitrile (160 mL, 1:1) and driedat 50° C. for overnight to give the title compound (19.2 g, 94%) as asolid form identified herein as polymorphic form D. ¹H NMR: 2.69 (3H,s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (1H,d), 6.28 (1H, d), 6.67 (1H, dd), 7.05-7.23 (2H, m), 7.29 (1H, t), 7.43(1H, d), 7.56 (1H, d), 8.21 (2H, s), 8.81 (1H, s), 9.47 (1H, s), 9.52(1H, s), m/z: ES⁺ MH⁺ 500.26.

Example 28 (Alternative Synthesis 2)N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

To a stirred solution ofN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine(Intermediate 100, 10g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at0° C. was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). Themixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28mmol) was added. The resulting mixture was heated to 65° C. for 10 h.The mixture was then cooled to r.t. and CH₃OH (40 mL) and water (70 mL)were added. The resulting mixture was stirred overnight. The resultingsolid was collected by filtration, washed with water (25 mL) and driedat 50° C. for 12 h to give the title compound (7.0 g, 94%) as a solidform identified herein as polymorphic Form D. ¹H NMR: 2.69 (3H, s) 2.83(6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d)6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d)8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES⁺ MH⁺ 500.26.

Example 28AN-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamidemesylate salt

Procedure 1:

To a stirred solution ofN-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide(Example 28, 20g, 36.63 mmol) in ethanol (120 mL) and EtOAc (80 mL) at70° C. was added methane sulfonic acid (3.59 g, 36.63 mmol) as asolution in EtOAc (40 mL). The resulting mixture was stirred for 1.5h.The resulting solid was collected by filtration and dried at 80° C.under vacuum overnight to give the title salt (20.5 g, 94%) in a solidform defined herein as polymorphic Form B for this salt.

Procedure 2:

To a stirred solution ofN-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide(Example 28, 5g, 9.11 mmol) in acetone (45.5 mL) and water (4.55 mL) at50° C. was added methane sulfonic acid (0.893 g, 9.11 mmol) as asolution in acetone (4.55 mL). The resulting mixture was stirred for1.5h. The resulting solid was collected by filtration and dried at 80°C. under vacuum overnight to give the title salt (4.9 g, 94%) in a solidform defined herein as polymorphic Form B for this salt; ¹H NMR(acetone-d⁶): 2.72 (3H, s), 2.96 (3H, s), 3.01 (6H, s), 3.58 (3H, t),3.87-3.90 (7H, m), 5.76 (1H, dd), 6.38-6.53 (2H, m), 7.12 (1H, t), 7.20(1H, t), 7.29 (1H, s), 7.40 (2H, t), 8.07-8.16 (3H, m), 8.56 (1H, s),9.30 (1H, s), 9.60 (1H, s), 9.66 (1H, s); m/z: ES⁺ MH⁺ 500.26.

Procedure 3:

Polymorphic Form A ofN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamidemesylate salt was prepared in a similar manner as described above on a˜50 mg scale, except that acetonitrile was used as the solvent.Specifically, ˜9.6 mg methanesulfonic acid was dissolved into a minimumvolume of acetonitrile. ˜50 mgN-(2-{2-dimethylamino-ethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)-prop-2-enamidewas also dissolved into a minimum volume of acetonitrile and then theresulting solution was added to the methanesulfonic acid solution.Formation of a solid resulted upon addition. This solid was collected byfiltration and was air-dried and then analysed. The particular solidform produced in this experiment was designated as Polymorphic Form Afor this salt.

Example 29N-(5-{[5-Cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.035 mL, 0.44 mmol) in CH₂Cl₂ (1 mL)was added to a mixture of2-{[5-amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]-amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile(Intermediate 102, 171 mg, 0.36 mmol) and DIPEA (0.120 mL, 0.73 mmol) inCH₂Cl₂ (3 mL) at 0° C., then the mixture was stirred at 0° C. for 1 h.The mixture was then diluted with CH₂Cl₂, washed twice with sat. NaHCO₃,and then water, then dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ gavethe title compound (68 mg, 36%) as a yellow solid; ¹H NMR: (100° C.)2.22 (6H, s), 2.40 (2H, t), 2.76 (3H, s), 2.98 (2H, t), 3.77 (3H, s),3.90 (3H, s), 5.69 (1H, dd), 6.17 (1H, dd), 6.40 (1H, dd), 7.02-7.06(2H, m), 7.21-7.25 (1H, m), 7.49 (1H, d), 8.23 (1H, d), 8.45 (1H, s),8.47 (1H, s), 8.63 (1H, s), 8.86 (1H, s), 9.59 (1H, s); m/z: ES⁺ MH⁺525.32.

Example 30N-(2-{(3R)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (53.4 mg, 0.59 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred mixture of4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 103, 270 mg, 0.59 mmol) and DIPEA (0.112 mL, 0.65 mmol) inCH₂Cl₂ (10 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1.5 h and was then diluted with CH₂Cl₂ (25 mL) and washedwith sat. NaHCO₃ (50 mL). The aqueous washes were extracted with CH₂Cl₂(2×25 mL). The combined organic solutions were then dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-4% 7Nmethanolic ammonia in CH₂Cl₂ provided the title compound mixed togetherwith diacylated material. This material was dissolved in CH₂Cl₂ andtriturated with diethyl ether. The resulting precipitate was collectedby filtration, washed with diethyl ether (10 mL) and air dried to giveimpure product (120 mg) as a yellow solid. This solid was purified bycrystallisation from CH₃CN to give the title compound (47 mg, 0.092mmol, 16%) as a yellow solid. All the residues were combined,concentrated in vacuo and crystallised from CH₃CN to give a second cropof the title compound (26 mg, 0.051 mmol, 9%) as a yellow solid. Totalyield of title compound=73 mg, 24%; ¹H NMR: (CDCl₃) 1.87-1.99 (1H, m),2.11-2.24 (1H, m), 2.30 (6H, s), 2.83-2.95 (1H, m), 3-3.19 (4H, m), 3.88(3H, s), 3.99 (3H, s), 5.75 (1H, dd), 6.34 (1H, dd), 6.44 (1H, dd), 6.79(1H, s), 7.20 (1H, d), 7.23-7.32 (2H, m) partially obscured by CDCl₃peak, 7.37-7.42 (1H, m), 7.67 (1H, s), 8.08 (1H, d), 8.38 (1H, d), 8.46(1H, s), 9.00 (1H, s), 9.71 (1H, s); m/z: ES⁺ MH⁺ 512.26.

Example 31N-{5-[5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[methyl-(2-morpholin-4-ylethyl)amino]phenyl}prop-2-enamide

Acryloyl chloride (0.413 mL, 1M in THF, 0.41 mmol) was added dropwise toa slurry ofN⁴-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5-methoxy-N¹-methyl-N¹-(2-morpholin-4-ylethyl)benzene-1,2,4-triamine(Intermediate 105, 298 mg, 0.59 mmol) and DIPEA (0.153 mL, 0.88 mmol) inTHF (5 mL) at −10° C. over a period of 2 minutes under N₂. The mixturewas stirred at 0° C. for 10 minutes and then allowed to warm to r.t.over 20 minutes. The mixture was cooled again to −10° C. and furtheracryloyl chloride (0.103 mL, 1M in THF, 0.103 mmol) was added dropwise.The slurry was stirred at 0° C. for a further 10 minutes, then allowedto warm to r.t. over 20 minutes. The mixture was then concentrated invacuo and the residue was dissolved in CH₂Cl₂ (5 mL). This solution waswashed with sat. NaHCO₃ (2 mL), dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH₂Cl₂gave a gum. This gum was dissolved in EtOAc (1 mL), and diethyl ether(˜1 mL) was added until just oiling out. The mixture was then stirredfor 3 days, filtered and the collected solid was dried by suction togive the title compound (193 mg, 59%) as a cream crystalline solid; ¹HNMR: 2.29-2.38 (4H, m), 2.41 (2H, t), 2.74 (3H, s), 3.03 (2H, t),3.49-3.61 (4H, m), 3.78 (3H, s), 5.72 (1H, d), 6.18 (1H, m), 6.60 (1H,m), 7.00 (1H, s), 7.10 (1H, m), 7.27-7.38 (1H, m), 8.25 (1H, s), 8.40(2H, m), 8.65 (1H, s), 8.82 (1H, d), 8.95 (1H, s), 9.28 (1H, s); m/z:ES⁺ MH⁺ 563.

Example 32N-(5-{[5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl]amino}-4-methoxy-2-{methyl-[2-(4-methylpiperazin-1-yl)ethyl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (0.028 mL, 0.35 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred mixture ofN⁴-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5-methoxy-N¹-methyl-N¹-[2-(4-methylpiperazin-1-yl)ethyl]benzene-1,2,4-triamine(Intermediate 107, 0.174g, 0.33 mmol) in CH₂Cl₂ (2.5 mL) under N₂. Themixture was then stirred at r.t. for 1 h and was then diluted withCH₂Cl₂ (25 mL). This solution was washed with sat. NaHCO₃ (25 mL) andthe aqueous wash solution was extracted with CH₂Cl₂ (20 mL). Thecombined organic solutions were dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 0-8% CH₃OH in CH₂Cl₂ gave the titlecompound (0.12 g, 63%) as a beige foam; ¹H NMR: (CDCl₃) 2.31 (3H, s),2.35-2.6 (10H, m), 2.67 (3H, s), 3.00 (2H, t), 3.88 (3H, s), 5.64-5.82(1H, m), 6.31-6.50 (2H, m), 6.79 (1H, s), 6.91 (1H, t), 7.29 (1H, t),7.48 (1H, s), 8.47 (1H, s), 8.54 (2H, t), 8.94 (1H, s), 9.15 (1H, s),9.38 (1H, s); m/z: ES⁺ MH⁺ 576.59.

Example 33N-(4-Methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

A solution of acryloyl chloride (58.4 mg, 0.64 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture of4-methoxy-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 110, 286 mg, 0.64 mmol) and DIPEA (0.134 mL, 0.77 mmol) inCH₂Cl₂ (20 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1.5 h at 0° C. More DIPEA was added (30 μL) then moreacryloyl chloride (20 mg) was added dropwise as a solution in CH₂Cl₂ (1mL). This mixture was stirred for 2 h and then diluted with CH₂Cl₂ (50mL). This solution was washed with sat. NaHCO₃ solution (2×25 mL) andthen the combined aqueous washes were extracted with CH₂Cl₂ (2×25 mL).The combined organic solutions were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The resulting gum was triturated with diethylether to give a solid which was collected by filtration and dried invacuo. Purification by FCC, eluting with 0-8% 7N methanolic ammonia inCH₂Cl₂ gave the title compound (55 mg, 17%) as a light grey solid aftertrituration with diethyl ether (with a few drops of CH₃OH); ¹H NMR: 2.27(3H, s), 2.53-2.59 (4H, m), 2.85-2.91 (4H, m), 3.87 (3H, s), 3.91 (3H,s), 5.75 (1H, d), 6.24 (1H, d), 6.67 (1H, dd), 6.89 (1H, s), 7.15-7.28(3H, m), 7.53 (1H, d), 7.89 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.58(1H, s), 8.81 (1H, s), 9.07 (1H, s); m/z: ES⁺ MH⁺ 498.58.

Example 34N-(5-{[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{3-dimethylaminoazetidin-1-yl}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.049 mL, 0.60 mmol) in CH₂Cl₂ (0.5 mL)was added dropwise to a mixture ofN-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine(Intermediate 112, 260 mg, 0.54 mmol) in CH₂Cl₂ (9 mL). This mixture wasstirred for 1 h and then loaded onto a SCX column. The column was washedwith CH₃OH and the desired product was then eluted from the column using2M methanolic ammonia. Appropriate fractions were concentrated in vacuoto give a brown gum. Purification by FCC, eluting with 1-10% CH₃OH inCH₂Cl₂ (containing 1% concentrated aqueous ammonia) gave the titlecompound (214 mg, 74%) as a yellow solid after trituration with CH₃OH(0.5 mL) using an ultrasound bath for 2 mins; ¹H NMR: 2.10 (6H, s),3.03-3.14 (1H, m), 3.59 (2H, t), 3.77 (3H, s), 3.90 (3H, s), 3.97 (2H,t), 5.66 (1H, dd), 6.16 (1H, dd), 6.23 (1H, s), 6.46 (1H, dd), 7.12 (1H,t), 7.23 (1H, t), 7.44-7.54 (2H, m), 8.20-8.38 (3H, m), 8.51 (1H, s),9.21 (1H, s); m/z: ES⁺ MH⁺ 532.

Example 35N-(2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (0.024 mL, 0.30 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred solution of4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 114, 130 mg, 0.28 mmol) in CH₂Cl₂ (5 mL), which was cooledin an ice/brine bath to approx 0° C. The mixture was stirred for 1 h,then diluted with CH₂Cl₂ (50 mL) and CH₃OH (to fully dissolve suspensionthat had formed). This solution was then washed with sat. NaHCO₃ (100mL) which had been diluted with water (10 mL). The aqueous wash solutionwas then extracted with CH₂Cl₂ (2×50 mL) and the combined organicsolutions were dried (MgSO₄) and concentrated in vacuo. Purification byFCC, eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave a dark brownsolid. This solid was heated in CH₃CN and isolated by vacuum filtration,to give the title compound (45 mg, 31%) as a pale brown solid. Themother liquors were concentrated in vacuo and also retained as a secondbatch of the title compound (30 mg, 21%) as a darker brown solid. Totalyield of title compound=75 mg, 52%; ¹H NMR: 2.08 (6H, s), 2.34 (3H, s),3-3.1 (1H, m), 3.55 (2H, t), 3.83 (3H, s), 3.88 (3H, s), 3.93 (2H, t),5.65 (1H, dd), 6.15 (1H, dd), 6.24 (1H, s), 6.44 (1H, dd), 7.13 (1H, t),7.21 (1H, t), 7.47 (1H, d), 7.66 (1H, s), 7.81 (1H, s), 7.99 (1H, s),8.17 (1H, s), 8.37 (1H, d), 9.19 (1H, s); m/z: ES⁺ MH⁺ 512.14.

Example 36N-(2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (0.044 mL, 0.54 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture of4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 116, 240 mg, 0.54 mmol) and DIPEA (0.104 mL, 0.60 mmol) inCH₂Cl₂ (5 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1 h and was then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (38 mg, 14%) as ayellow solid after trituration with diethyl ether and washing of theresulting solid with a small volume of CH₃OH; ¹H NMR: 2.10 (6H, s), 3.08(1H, t), 3.56 (2H, t), 3.86 (3H, s), 3.89 (3H, s), 3.96 (2H, t), 5.69(1H, dd), 6.18-6.29 (2H, m), 6.52 (1H, dd), 7.14 (1H, d), 7.17-7.28 (2H,m), 7.51 (1H, d), 7.75 (1H, s), 7.98 (1H, s), 8.26 (1H, d), 8.34 (2H,d), 9.29 (1H, s); m/z: ES⁺ MH⁺ 498.44.

Example 37N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{3-dimethylaminoazetidin-1-yl}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.057 mL, 0.70 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred solution ofN-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine(Intermediate 118, 310 mg, 0.67 mmol) and DIPEA (0.127 mL, 0.73 mmol) inCH₂Cl₂ (40 mL), which was cooled in an ice/water bath to 0° C. Themixture was stirred while in the ice/water bath for 1 h and was thenallowed to warm to r.t. The mixture was then held at r.t. for 18 h, andwas then diluted with CH₂Cl₂ (100 mL). This solution was then washedwith sat. NaHCO₃ (200 mL) and the aqueous wash solution was extractedwith CH₂Cl₂ (2×100 mL). The combined organic solutions were dried(MgSO₄) and concentrated in vacuo. Purification by FCC, eluting with0-5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound togetherwith an impurity (172 mg, 50%) as a pale yellow solid. 120 mg of thismaterial was purified by crystallisation from CH₃CN to give the titlecompound (85 mg, 0.164 mmol) as a yellow solid without evidence of theimpurity by NMR analysis. The mother liquors from the crystallizationand a further impure fraction from the FCC (containing a 75:25 mixtureof product:starting material) were combined, concentrated in vacuo andwas purified by crystallisation from CH₃CN to give more of the titlecompound (40 mg, 12%) as a tan solid; ¹H NMR: 2.09 (6H, s), 3.03-3.12(1H, m), 3.58 (2H, t), 3.78 (3H, s), 3.96 (2H, t), 5.66 (1H, dd), 6.16(1H, dd), 6.25 (1H, s), 6.46 (1H, dd), 7.07 (1H, t), 7.16 (1H, t), 7.45(1H, d), 7.48 (1H, s), 8.24 (1H, s), 8.27-8.31 (1H, br s), 8.31 (1H, s),8.46 (1H, d), 9.22 (1H, s), 11.79 (1H, s); m/z: ES⁺ MH⁺ 518.23.

Example 38N-{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[(3R)-3-dimethylaminopyrrolidin-1-yl]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.027 mL, 0.33 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a mixture of2-({5-amino-4-[(3R)-3-(dimethylamine)pyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-5-carbonitrile(Intermediate 120, 155 mg, 0.33 mmol) and DIPEA (0.063 mL, 0.36 mmol) inCH₂Cl₂ (10 mL), which was cooled in an ice/water bath. The mixture wasstirred for 2 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave a foam. Concentration from a mixtureof CH₃OH/CH₂Cl₂ gave a solid which was triturated in diethyl ether andcollected by filtration to give the title compound (95 mg, 55%) as ayellow solid; ¹H NMR: (100° C.) 1.82 (1H, dq), 2.08 (1H, ddd), 2.22 (6H,s), 2.8-2.89 (1H, m), 3.19-3.45 (4H, m), 3.78 (3H, s), 5.63 (1H, dd),6.16 (1H, dd), 6.44 (1H, dd), 6.61 (1H, s), 7.12 (1H, td), 7.34-7.46(1H, m), 7.54 (1H, s), 8.33 (1H, d), 8.64 (1H, s), 8.77 (1H, d), 8.90(2H, s), 8.96 (1H, s); m/z: ES⁺ MH⁺ 524.57.

Example 39N-{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[2-dimethylaminoethyl-methylamino]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.087 mL, 1M, THF, 0.09 mmol) was addeddropwise to a mixture of2-{[5-amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]-amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile(Intermediate 121, 0.036 g, 0.08 mmol) and DIPEA (0.017 mL, 0.09 mmol)in THF (5 mL) which was cooled to 0° C. The mixture was stirred at 0° C.for 3 h, then concentrated in vacuo. Purification by FCC, eluting with0-20% CH₃OH in CH₂Cl₂ have crude product which appeared to contain thehydrochloride salt of DIPEA. The material was dissolved in CH₂Cl₂ (10mL) and stirred with sat. NaHCO₃ solution (10 mL). The phases wereseparated and the organic solution was concentrated in vacuo to give thetitle compound (24 mg, 60%) as a yellow gum; ¹H NMR: (CDCl₃) 2.22 (6H,s), 2.26 (2H, dd), 2.67 (3H, d), 2.77-2.86 (2H, m), 3.81 (3H, s), 5.61(1H, dd), 6.16-6.35 (2H, m), 6.76 (1H, s), 6.88 (1H, d), 7.23 (1H, s),7.65 (1H, s), 8.50 (2H, dd), 8.59 (1H, s), 9.02 (1H, s), 9.28 (1H, s),10.08 (1H, s); m/z: ES⁺ MH⁺ 512.29.

Example 40N-{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4-methoxyphenyl}prop-2-enamide

A solution of acryloyl chloride (0.025 mL, 0.31 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred solution of2-{[5-amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile(Intermediate 122, 136 mg, 0.30 mmol) in CH₂Cl₂ (15 mL), which wascooled in an ice bath to approximately 0° C. The mixture was stirred for1 h, and was then diluted with iii CH₂Cl₂ (50 mL) and methanol (to fullydissolve suspension). This solution was then washed with sat. NaHCO₃(100 mL) which had been diluted with water (10 mL). The aqueous washsolution was then extracted with CH₂Cl₂ (2×50 mL) and the combinedorganic solutions were dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂gave the title compound (136 mg, 89%) as a yellow solid; ¹H NMR: 2.10(6H, s), 3.05-3.13 (1H, m), 3.62 (2H, t), 3.74 (3H, s), 4.00 (2H, s),5.67 (1H, d), 6.17 (1H, d), 6.27 (1H, s), 6.45 (1H, dd), 7.16 (1H, brs), 7.25 (1H, s), 7.42 (1H, br s), 7.95 (1H, br s), 8.68 (1H, s), 8.87(1H, br s), 8.91 (1H, s), 9.28 (1H, s), 9.32 (1H, br s); m/z: ES⁺ MH⁺510.18.

Example 41N-(2-{(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

Acryloyl chloride (41.3 mg, 0.46 mmol) in THF (1 mL) was added dropwiseto a stirred solution of4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 123, 195 mg, 0.42 mmol) in THF (3 mL), cooled in anice/methanol bath to approximately −15° C. Upon slow addition of theacryloyl chloride a precipitate immediately formed. The mixture wasstirred for 1 h while being gradually warmed to 0° C. The mixture wasthen diluted with CH₂Cl₂ (50 mL) and washed with sat. NaHCO₃ (50 mL).The resulting aqueous solution was extracted with CH₂Cl₂ (2×25 mL). Thecombined organic solutions were dried (MgSO₄) and concentrated ontosilica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia inCH₂Cl₂ gave crude solid product after concentration of appropriatefractions in vacuo. This solid was dissolved in the minimum amount ofhot CH₂Cl₂ and triturated with diethyl ether to give the title compound(115 mg, 53%) as a white solid; ¹H NMR (CDCl₃) 1.77-1.96 (2H, m),2.15-2.26 (1H, m), 2.29 (3H, s), 2.26-2.37 (1H, m), 2.73 (1H, d), 2.80(1H, d), 2.83-2.90 (1H, m), 2.95 (1H, td), 3.21 (1H, t), 3.57-3.68 (1H,m), 3.88 (3H, s), 4.00 (3H, s), 5.68-5.74 (1H, m), 6.45 (2H, d), 6.81(1H, s), 7.20 (1H, d), 7.23-7.31 (2H, m) partially obscured under CDCl₃signal, 7.37-7.43 (1H, m), 7.71 (1H, s), 8.02-8.10 (1H, m), 8.38 (1H,d), 9.09 (1H, s), 9.46 (1H, s), 9.85 (1H, s); m/z: ES⁺ MH⁺ 524.25.

Example 42N-(2-[2-Dimethylaminoethyl-methylamino]-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (0.354 mL, 4.35 mmol) in CH₂Cl₂ (5 mL)was added dropwise to a mixture ofN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine(Intermediate 125, 1.9 g, 4.35 mmol) in CH₂Cl₂ (100 mL), which wascooled in an ice/water bath. The resulting mixture was stirred for 1 hand then washed with sat. NaHCO₃. The resulting organic solution wasdried (Na₂SO₄) and concentrated in vacuo. Purification by FCC, elutingwith 1.5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (1.069g, 50%) as an oil which crystallised on standing to give a creamcrystalline solid. Some later fractions from the FCC which had a browncolour were concentrated and re-chromatographed to give more of thetitle compound (334 mg, 16%) as a pale brown oil which crystallised onstanding to give a tan-coloured crystalline solid. Total yield: 1.403 g,66%; ¹H NMR: 1.69-1.77 (2H, m), 1.88-1.97 (2H, m), 2.21 (6H, s), 2.29(2H, t), 2.71 (3H, s), 2.88 (2H, t), 3.02 (2H, t), 3.84 (3H, s), 4.09(2H, t), 5.74 (1H, dd), 6.24 (1H, dd), 6.40 (1H, dd), 6.97-7.02 (2H, m),7.87 (1H, s), 8.13 (1H, s), 8.31 (1H, d), 8.85 (1H, s), 10.08 (1H, s);m/z: ES⁺ MH⁺ 491.34.

Example 43N-(2-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (26 mg, 0.29 mmol) in THF (1 mL) wasadded dropwise to a stirred solution of4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 132, 120 mg, 0.26 mmol) in THF (3 mL), which was cooled inan ice/methanol bath to approx −15° C. The mixture was stirred for 1 h,gradually warming to 0° C. The mixture was then diluted with CH₂Cl₂ (50mL) and washed with sat. NaHCO₃ (50 mL). The resulting aqueous washsolution was further extracted with CH₂Cl₂ (2×25 mL) and the combinedorganic solutions were then dried (MgSO₄) and concentrated in vacuo ontosilica. Part-purification was achieved by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ and impure product containing fractionswere combined and concentrated in vacuo. Purification by FCC, elutingwith 0-2% 7N methanolic ammonia in CH₂Cl₂ and then eluting with 0-3%CH₃OH in CH₂Cl₂ gave the title compound (19 mg, 14%) as a cream foam; ¹HNMR (CDCl₃): 1.82-1.97 (4H, m), 2.00-2.06 (2H, m), 2.13-2.24 (1H, s),2.25-2.39 (1H, m), 2.29 (3H, s), 2.67-2.98 (4H, m), 3.17-3.26 (3H, m),3.66 (1H, br s), 3.86 (3H, s), 4.18 (2H, t), 5.64-5.71 (1H, m),6.30-6.47 (2H, m), 6.78 (1H, s), 6.81 (1H, d), 7.44 (1H, s), 8.06 (1H,s), 8.34 (1H, d), 9.24 (1H, s), 9.40 (1H, s); m/z: ES⁺ MH⁺ 515.15.

Example 44N-(2-{(3R)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (32 mg, 0.36 mmol) in CH₂Cl₂ (1 mL) wasadded dropwise to a stirred solution of4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 134, 152 mg, 0.34 mmol) in CH₂Cl₂ (15 mL), which wascooled in an ice/water bath. The solution was stirred for 10 minuteswhile cooled by the ice bath, and was then allowed to warm to r.t. thenstirred for 1 h. The mixture was then diluted with CH₂Cl₂ and washedwith sat. NaHCO₃ and then brine. The organic solution was then dried(MgSO₄) and concentrated in vacuo. Purification by FCC, eluting with0-5% 7N methanolic ammonia in CH₂Cl₂ gave crude product (100 mg) as abeige solid after trituration with diethyl ether. CH₃CN (˜3 mL) was thenadded to the crude product and the resulting slurry was stirred at 50°C. for 4 h. After cooling to r.t. the suspended solid was collected byfiltration, washed with CH₃CN and dried at 45° C. overnight to give thetitle compound (72 mg, 42%) as a yellow solid; ¹H NMR: 1.68-1.81 (3H,m), 1.89-1.98 (2H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.66-2.74 (1H,m), 3.00-3.05 (2H, m), 3.13-3.21 (3H, m), 3.31-3.38 (1H, m), 3.86 (3H,s), 4.09 (2H, t), 5.70 (1H, dd), 6.21 (1H, dd), 6.48-6.56 (2H, m), 6.96(1H, d), 7.72 (1H, s), 8.03 (2H, d), 8.27 (1H, d), 9.30 (1H, s); m/z:ES⁺ MH⁺ 503.67.

Example 45N-(4-Methoxy-2-{1-methyl-3,6-dihydro-2H-pyridin-4-yl}-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (30 μL, 0.37 mmol) in CH₂Cl₂ (2 mL) wasadded dropwise over 5 minutes to4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 136, 154 mg, 0.36 mmol) in CH₂Cl₂ (5 mL), which was cooledin an ice/CH₃OH bath. The mixture was then stirred for 0.5h. The mixturewas then diluted with 10% CH₃OH/CH₂Cl₂ and the resulting solution waswashed with sat. NaHCO₃, dried (MgSO₄) and then concentrated in vacuo.Purification by FCC, eluting with 0-10% methanolic ammonia in CH₂Cl₂gave the title compound (104 mg, 60%) as an pale yellow solid aftertrituration with diethyl ether/heptane; ¹H NMR: 1.76-1.84 (2H, m),1.91-1.98 (2H, m), 2.27 (3H, s), 2.32-2.39 (2H, m), 2.48-2.56 (2H, m),2.96-2.99 (2H, m), 3.08 (2H, t), 3.90 (3H, s), 4.11 (2H, t), 5.65-5.76(2H, m), 6.21 (1H, d), 6.49 (1H, dd), 6.84 (1H, s), 7.07 (1H, d), 7.84(1H, s), 8.10 (1H, s), 8.32-8.37 (2H, m), 9.33 (1H, s); m/z: ES⁺ MH⁺486.73.

Example 46N-(2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (22.5 mg, 0.25 mmol) in CH₂Cl₂ (1 mL)was added dropwise to a stirred solution of4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 139, 108 mg, 0.25 mmol) in CH₂Cl₂ (12 mL), which wascooled in an ice/water bath. The solution was stirred for 10 minuteswhile being cooled by the bath, was then allowed to warm to r.t. and wasthen stirred for 1 h. The mixture was then diluted with CH₂Cl₂ andwashed with sat. NaHCO₃, brine and was then dried (MgSO₄). Purificationby FCC, eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (56 mg, 46%) as a brown solid after trituration with diethylether; ¹H NMR: 1.75-1.82 (2H, m), 1.90-1.97 (2H, m), 2.08 (6H, s),2.98-3.09 (3H, m), 3.54 (2H, t), 3.85 (3H, s), 3.93 (2H, t), 4.09 (2H,t), 5.69 (1H, dd), 6.18-6.25 (2H, m), 6.49 (1H, dd), 6.95 (1H, d), 7.70(1H, s), 7.89 (1H, s), 8.03 (1H, s), 8.26 (1H, d), 9.24 (1H, s); m/z:ES⁺ MH⁺ 489.63.

Example 47N-(4-Methoxy-2-{8-methyl-2,8-diazaspiro[3.4]octan-2-yl}-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (42 μL, 0.52 mmol) in CH₂Cl₂ (1 mL) wasadded dropwise to4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 141, 240 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) inCH₂Cl₂ (10 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1 h and then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (135 mg, 50%) as ayellow solid after trituration with CH₃CN; ¹H NMR: 1.61-1.74 (2H, m),1.73-1.85 (2H, m), 1.87-1.99 (2H, m), 2.03 (2H, t), 2.35 (3H, s), 2.61(2H, t), 3.01 (2H, t), 3.60 (2H, d), 3.84 (3H, s), 3.89 (2H, d), 4.09(2H, t), 5.70 (1H, d), 6.14-6.30 (2H, m), 6.47 (1H, dd), 6.95 (1H, d),7.73 (1H, s), 7.83 (1H, s), 8.05 (1H, s), 8.26 (1H, d), 9.26 (1H, s);m/z: ES⁺ MH⁺ 515.7.

Example 48N-(4-Methoxy-2-{1-methyl-3,6-dihydro-2H-pyridin-4-yl}-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (37 μL, 0.45 mmol) in CH₂Cl₂ (2.32 mL)was added dropwise over 5 minutes to4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 143, 189 mg, 0.43 mmol) in CH₂Cl₂ (5.8 mL), which wascooled in an ice/CH₃OH bath. The mixture was stirred for 0.5 h and wasthen diluted with 10% CH₃OH/CH₂Cl₂. The resulting solution was washedwith sat. NaHCO₃, dried (MgSO₄) and concentrated in vacuo. Purificationby FCC, eluting with 0-20% CH₃OH in CH₂Cl₂ gave the title compound (67mg, 32%) as an pale yellow solid after trituration with diethyl ether;¹H NMR: 2.29 (3H, s), 2.36-2.41 (2H, m), 2.53-2.58 (2H, m), 2.98-3.02(2H, m), 3.90 (3H, s), 3.91 (3H, s), 5.69-5.73 (2H, m), 6.22 (1H, dd),6.52 (1H, dd), 6.86 (1H, s), 7.20-7.28 (3H, m), 7.52-7.55 (1H, m), 7.88(1H, s), 8.33-8.37 (2H, m), 8.43 (1H, s), 8.45 (1H, s), 9.34 (1H, s);m/z: ES⁺ MH⁺ 495.70.

Example 49N-(4-Methoxy-2-{8-methyl-2,8-diazaspiro[3,4]octan-2-yl}-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (24 μL, 0.30 mmol) in CH₂Cl₂ (1 mL) wasadded dropwise to4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 146, 140 mg, 0.30 mmol) and DIPEA (57 μL, 0.33 mmol) inCH₂Cl₂ (10 mL), which was cooled in an ice/water bath. The mixture wasstirred for 1 h and was then washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (43 mg, 28%) as abeige solid after trituration with CH₃CN; ¹H NMR: 1.63-1.76 (2H, m),2.00-2.10 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.64 (2H, d), 3.86 (3H,s), 3.89 (3H, s), 3.93 (2H, d), 5.70 (1H, dd), 6.21 (1H, dd), 6.26 (1H,s), 6.50 (1H, dd), 7.13 (1H, d), 7.16-7.29 (2H, m), 7.51 (1H, d), 7.73(1H, s), 7.93 (1H, s), 8.26 (1H, d), 8.31-8.39 (2H, m), 9.24 (1H, s);m/z: ES⁺ MH⁺ 524.7.

Example 50N-(2-{(3S)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

A solution of acryloyl chloride (1M in CH₂Cl₂, 0.36 mL, 0.36 mmol) wasadded dropwise to a solution of4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 148, 183 mg, 0.40 mmol) in CH₂Cl₂ (5 mL) at −10° C. over aperiod of 2 minutes under an atmosphere of N₂. The resulting mixture wasstirred at 0° C. for 10 minutes and was then allowed to warm to r.t.over 20 minutes. The mixture was then washed with sat. NaHCO₃ (2 mL),dried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 3-25% CH₃OH in CH₂Cl₂ gave an oil which later crystallised. Thissolid was triturated and washed with EtOAc (3 mL) to give the titlecompound (67 mg, 33%) as a pale yellow solid; ¹H NMR: 1.77 (1H, m), 2.08(1H, s), 2.18 (6H, s), 2.72 (1H, m), 3.17 (1H, s), 3.21 (2H, d),3.32-3.45 (1H, m), 3.87 (3H, s), 3.89 (3H, s), 5.70 (1H, d), 6.22 (1H,d), 6.48-6.58 (1H, m), 6.59 (1H, s), 7.20 (3H, m), 7.51 (1H, d), 7.76(1H, s), 8.17 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.39 (1H, s), 9.33(1H, s); m/z: ES⁺ MH⁺ 512.7.

Example 51N-{4-Methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

A solution of acryloyl chloride (20 μL, 0.25 mmol) was added dropwise to4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine(Intermediate 150, 180 mg, 0.42 mmol) and triethylamine (73 lilt, 0.53mmol) in THF (3 mL) at −5° C. over a period of 1 minute under anatmosphere of N₂. The resulting mixture was stirred at 0° C. for 0.25h.The reaction was judged to be incomplete so further acryloyl chloride(10 μL, 0.125 mmol) was added dropwise and the mixture was stirred at 0°C. for a further 15 minutes. The mixture was then concentrated in vacuoand the resulting residue was dissolved in CH₂Cl₂ (5 mL) plus a fewdrops of CH₃OH. This solution was washed with sat. NaHCO₃ (2 mL), dried(MgSO₄) and filtered through a 1 g silica pad, eluting with 4:1CH₂Cl₂-CH₃OH. Eluent that contained desired product was concentrated invacuo. Purification by FCC, eluting with 5-20% CH₃OH in CH₂Cl₂ gave thetitle compound (31 mg, 14%) as a cream crystalline solid; ¹H NMR: 2.33(3H, s), 2.40 (2H, s), 2.57 (2H, d), 3.03 (2H, s), 3.89 (3H, s), 5.70(2H, m), 6.17 (1H, m), 6.46 (1H, m), 6.88 (1H, s), 7.09 (1H, t), 7.32(1H, d), 7.47 (1H, t), 8.12 (1H, s), 8.21 (1H, s), 8.39 (1H, d), 8.51(1H, d), 8.81 (2H, m), 9.36 (1H, s); m/z: ES⁺ MH⁺ 482.

Example 52N-{2-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

A solution of acryloyl chloride (64 μL, 0.79 mmol) in CH₂Cl₂ (4 mL) wasadded dropwise over 10 minutes to4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine(Intermediate 153, 336 mg, 0.76 mmol) in CH₂Cl₂ (11 mL), which wascooled in an ice/CH₃OH bath. The mixture was stirred for 0.5h, and wasthen diluted with 10% CH₃OH/CH₂Cl₂. The resulting solution was washedwith sat.NaHCO₃, dried (MgSO₄) and concentrated in vacuo. Purificationby FCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ gave the titlecompound (296 mg, 79%) as an orange solid after trituration with diethylether; ¹H NMR: 1.70-1.81 (1H, m), 2.05-2.13 (1H, m), 2.18 (6H, s),2.68-2.76 (1H, m), 3.17-3.27 (3H, m), 3.35-3.42 (1H, m), 3.84 (3H, s),5.67 (1H, dd), 6.17 (1H, dd), 6.51 (1H, dd), 6.56 (1H, s), 7.05 (1H,dd), 7.21 (1H, d), 7.40-7.45 (1H, m), 7.84 (1H, s), 8.02 (1H, s), 8.30(1H, d), 8.46 (1H, d), 8.76 (1H, s), 8.78 (1H, d), 9.35 (1H, s); m/z:ES⁺ MH⁺ 499.69.

Example 53N-{2-(3-Dimethylaminoazetidin-1-yl)-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

A solution of acryloyl chloride (49 μL, 0.60 mmol) in CH₂Cl₂ (2.77 mL)was added dropwise over 5 minutes to4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine(Intermediate 156, 246 mg, 0.57 mmol) in CH₂Cl₂ (8.3 mL), which wascooled in an ice/CH₃OH bath. The mixture was stirred for 0.5 h asn wasthen diluted with 10% CH₃OH/CH₂Cl₂. The resulting solution was washedwith sat. NaHCO₃, dried (MgSO₄) and concentrated in vacuo. Purificationby FCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ gave the titlecompound (182 mg, 66%) as a yellow solid after trituration with diethylether; ¹H NMR: 2.09 (6H, s), 3.04-3.12 (1H, m), 3.55-3.60 (2H, m), 3.83(3H, s), 3.96 (2H, t), 5.67 (1H, dd), 6.18 (1H, dd), 6.26 (1H, s), 6.48(1H, dd), 7.05 (1H, td), 7.20 (1H, d), 7.41-7.46 (1H, m), 7.71 (1H, s),8.00 (1H, s), 8.29 (1H, d), 8.43 (1H, br d), 8.75 (1H, s), 8.77 (1H, d),9.29 (1H, s); m/z: ES⁺ MH⁺ 485.69.

Example 54N-{2-[2-Dimethylaminoethyl-methylamino]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

A solution of acryloyl chloride (63 μL, 0.78 mmol) in CH₂Cl₂ (3.60 mL)was added dropwise over 5 minutes toN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,2,4-triamine(Intermediate 158, 320 mg, 0.74 mmol) in CH₂Cl₂ (10.8 mL), which wascooled in an ice/CH₃OH bath. The mixture was stirred for 0.5h, and wasthen diluted with 10% CH₃OH/CH₂Cl₂. The resulting solution was washedwith sat. NaHCO₃, dried (MgSO₄) and concentrated in vacuo. Purificationby FCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ gave the titlecompound (228 mg, 63%) as a pale pink solid after trituration withdiethyl ether; ¹H NMR: 2.22 (6H, s), 2.33 (2H, t), 2.74 (3H, s), 2.91(2H, t), 3.82 (3H, s), 5.73 (1H, dd), 6.19 (1H, dd), 6.41 (1H, dd),7.02-7.06 (2H, m), 7.25 (1H, d), 7.29-7.34 (1H, m), 8.17 (1H, s), 8.34(1H, d), 8.44 (1H, d), 8.75-8.79 (2H, m), 8.82 (1H, s), 10.06 (1H, brs); m/z: ES⁺ MH⁺ 487.72.

Example 55N-[2-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl]prop-2-enamide

A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 mL) wasadded dropwise to a stirred solution of4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine(Intermediate 160, 100 mg, 0.13 mmol) in THF (3 mL), which was cooled inan ice/CH₃OH bath to approximately −15° C. The mixture was stirred for 1h and allowed to warm to −0° C. The mixture was then diluted with CH₂Cl₂(50 mL) and the resulting solution was washed with sat. NaHCO₃ (50 mL).The aqueous solution was further extracted with CH₂Cl₂ (2×25 mL) and thecombined organic solutions were dried (MgSO₄) and concentrated in vacuoonto silica. Patrial purification by FCC, eluting with 0-3.5% 7Nmethanolic ammonia in CH₂Cl₂ provided some of the title compound.Further purification by FCC, eluting with 0-1.5% 7N methanolic ammoniain CH₂Cl₂ gave the title compound (33 mg, 49%) as a yellow solid; ¹HNMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d),2.39-2.48 (1H, m), 2.87 (1H, s), 3.11-3.20 (1H, m), 3.33-3.42 (2H, m),3.81 (3H, s), 4.26-4.34 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H,dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03(1H, s), 8.08 (1H, s), 8.30 (1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m),9.41 (1H, s); m/z: ES⁺ MH⁺ 511.16.

Example 56N-{4-Methoxy-2-[8-methyl-2,8-diazaspiro[3.4]octan-2-yl]-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

A solution of acryloyl chloride (0.766 mL, 0.77 mmol, 1.0 M in CH₂Cl₂)was added dropwise over 10 minutes to4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine(Intermediate 162, 333 mg, 0.73 mmol) in CH₂Cl₂ (6 mL), which was cooledin an ice/CH₃OH bath. The mixture was then stirred for 0.5h, thendiluted with 10% CH₃OH in CH₂Cl₂. The resulting solution was washed withsat. NaHCO₃, dried (MgSO₄) and concentrated in vacuo. Purification byFCC, eluting with 1-10% methanolic ammonia in CH₂Cl₂ gave the titlecompound (193 mg, 52%) as an beige solid after trituration with diethylether; ¹H NMR: 1.69 (2H, dt), 2.03-2.08 (2H, m), 2.38 (3H, s), 2.63 (2H,t), 3.65 (2H, d), 3.83 (3H, s), 3.94 (2H, d), 5.68 (1H, dd), 6.19 (1H,dd), 6.25 (1H, s), 6.47 (1H, dd), 7.06 (1H, td), 7.19 (1H, d), 7.44 (1H,dd), 7.67 (1H, s), 7.98 (1H, s), 8.29 (1H, d), 8.47 (1H, d), 8.75 (1H,s), 8.78 (1H, d), 9.25 (1H, s); m/z: ES⁺ MH⁺ 511.34.

Example 57N-(2-{(3R)-3-Dimethylaminopyrrolidin-1-yl}-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.604 mL, 1M in CH₂Cl₂, 0.60 mmol) wasadded dropwise to4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine(Intermediate 164, 268 mg, 0.60 mmol) in CH₂Cl₂ (10 mL) and 10 mL DMA,which was cooled to −5° C. The resulting mixture was stirred at −5° C.for 1 h and was then diluted with CH₂Cl₂ (100 mL). The resultingsolution was washed with sat. NaHCO₃ (25 mL), water (25 mL), and thensat. brine (4×25 mL), and was then concentrated in vacuo. Purificationby FCC, eluting with 0-30% CH₃OH in CH₂Cl₂ gave the title compound (135mg, 45%) as a beige solid; ¹H NMR (CDCl₃) 1.98 (1H, s), 2.18 (1H, d),2.94 (1H, s), 3.11 (4H, d), 3.88 (3H, s), 5.73 (1H, d), 6.40 (2H, d),6.76 (1H, s), 7.17 (1H, d), 7.22-7.24 (1H, m), 7.41-7.46 (1H, m), 7.62(1H, s), 8.16 (1H, s), 8.39 (1H, d), 8.45 (1H, s), 8.75 (1H, s), 8.86(1H, s), 9.56 (1H, s); m/z: ES⁺ MH⁺ 498.

Example 58N-(2-[3-Dimethylaminoazetidin-1-yl]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.522 mL, 1M in CH₂Cl₂, 0.52 mmol) wasadded dropwise to4-(3-dimethylaminoazetidin-1-yl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxy-benzene-1,3-diamine(Intermediate 166, 224 mg, 0.52 mmol) in CH₂Cl₂ (10 mL) and the mixturewas then stirred at −5° C. for 1 h. The mixture was then diluted withCH₂Cl₂ (100 mL), and the resulting solution was washed with sat. NaHCO₃(25 mL), water (25 mL), and then sat. brine (25 mL) and thenconcentrated in vacuo. Purification by FCC, eluting with 0-30% CH₃OH inCH₂Cl₂ gave the title compound (46 mg, 18%) as a beige solid; ¹H NMR:2.09 (6H, d), 3.09 (1H, s), 3.56 (2H, t), 3.85 (3H, s), 3.96 (2H, t),5.68 (1H, dd), 6.20 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.14 (2H,dt), 7.18 (1H, t), 7.40-7.46 (1H, m), 7.82 (1H, s), 7.90 (1H, s), 8.23(1H, d), 8.31 (1H, d), 8.38 (1H, d), 9.34 (1H, s), 11.76 (1H, s); m/z:ES⁺ MH⁺ 484.

Example 59N-(2-[2-Dimethylaminoethyl-methylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.584 mL, 1M in CH₂Cl₂, 0.58 mmol) wasadded dropwise toN¹-(2-dimethylaminoethyl)-N⁴-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N¹-methylbenzene-1,2,4-triamine(Intermediate 168, 252 mg, 0.58 mmol) in CH₂Cl₂ (10 mL) and the mixturewas then stirred at −5° C. for 1 h. The mixture was then diluted withCH₂Cl₂ (100 mL), and the resulting solution was washed with sat. NaHCO₃(25 mL), water (25 mL), and then sat. brine (25 mL), and was thenconcentrated in vacuo. Purification by FCC, eluting with 0-30% CH₃OH inCH₂Cl₂ gave the title compound (76 mg, 27%) as a white solid; ¹H NMR(CDCl₃) 2.25 (6H, s), 2.27-2.34 (3H, m), 2.69 (3H, s), 2.84-2.94 (2H,m), 3.87 (3H, s), 5.68 (1H, dd), 6.40 (1H, d), 6.48 (1H, dd), 6.78 (1H,s), 7.03 (1H, d), 7.08-7.20 (2H, m), 7.33 (1H, dd), 7.65 (1H, s), 8.12(1H, d), 8.26 (1H, d), 8.59 (1H, s), 9.74 (1H, s), 9.97 (1H, s), 10.24(1H, s); m/z: ES⁺ MH⁺ 486.

Example 60N-(4-Methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-[methyl-(2-methylaminoethyl)amino]phenyl)prop-2-enamide

A solution of tert-butylN-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-(prop-2-enoylamino)phenyl]-methylamino]ethyl]-N-methylcarbamate(Intermediate 170, 321 mg, 0.55 mmol) in CH₂Cl₂ (10 mL) and TFA (2 mL)was stirred at r.t. for 0.5 h and then concentrated in vacuo. Theresidue was dissolved in 10% CH₃OH/CH₂Cl₂. The resulting solution waswashed with sat. NaHCO₃, dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 0-20% CH₃OH in CH₂Cl₂ gave the titlecompound (110 mg, 41%) as a pale yellow solid after trituration withdiethyl ether; ¹H NMR: 2.35 (3H, s), 2.58-2.62 (2H, m), 2.71 (3H, s),2.85-2.89 (2H, m), 3.86 (3H, s), 3.92 (3H, s), 5.74 (1H, dd), 6.28 (1H,dd), 6.59 (1H, dd), 6.99 (1H, s), 7.15 (1H, t), 7.21-7.27 (2H, m), 7.53(1H, d), 7.87 (1H, s), 8.24 (1H, d), 8.32 (1H, d), 8.66 (1H, s), 9.16(1H, s), 10.33 (1H, s); m/z: ES⁺ MH⁺ 486.55.

Intermediate 1:4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(5-methyl-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A mixture ofN-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-5-methyl-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 2, 279 mg, 0.59 mmol), iron (198 mg, 3.55 mmol) and NH₄Cl(22.16 mg, 0.41 mmol) in ethanol (10.5 mL) and water (3.50 mL) washeated at reflux for 0.75h. Further NH₄Cl (22.16 mg, 0.41 mmol) and iron(198 mg, 3.55 mmol) were then added and the mixture was heated at refluxfor a further 1.5h. The mixture was then cooled, filtered, and thefiltrate was concentrated in vacuo. Purification by FCC, eluting with2-10% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (150 mg,57%) as a beige crystalline solid after trituration with THF and washingthe resulting solid with diethyl ether; ¹H NMR: 2.30 (3H, s), 2.40 (5H,m), 2.59 (2H, t), 3.01 (2H, d), 3.73 (3H, s), 4.27 (2H, s), 5.71 (1H,s), 6.63 (1H, s), 7.10 (1H, m), 7.35-7.49 (2H, m), 7.83 (1H, s), 8.27(1H, s), 8.50-8.63 (2H, m), 8.81 (1H, d); m/z: ES⁺ MH⁺ 442.

Intermediate 2:N-[2-Methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitro-phenyl]-5-methyl-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

A solution of 3-(2-chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine(Intermediate 5, 271 mg, 1.00 mmol), p-toluene sulphonic acidmonohydrate (271 mg, 1.43 mmol) and2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline(Intermediate 3, 250 mg, 0.95 mmol) were heated in 2-pentanol (12 mL) atreflux under N₂ for 30 h. The mixture was then concentrated in vacuo andthe residue was dissolved in CH₃OH. Purification by ion exchangechromatography (SCX column), eluting with 7M methanolic ammonia, gavethe title compound (283 mg, 63%) as an orange powder after triturationwith CH₃CN. ¹H NMR: 2.28-2.36 (5H, m), 2.44 (3H, s), 2.60 (2H, t), 3.00(2H, d), 4.00 (3H, d), 5.64 (1H, s), 6.97 (1H, s), 7.13 (1H, m), 7.40(1H, m), 8.27 (1H, s), 8.39 (1H, s), 8.53 (1H, d), 8.61 (1H, s), 8.83(1H, d), 8.87 (1H, s); m/z: ES⁻ MH⁻ 470.

Intermediate 3:2-Methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline

A mixture of 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 1.112 g,4.5 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine(1.004 g, 4.50 mmol) and K₂CO₃ (2.488 g, 18.00 mmol) was stirred in1,4-dioxane (20 mL) and water (5 mL). The mixture was purged with N₂ for0.25h. Tetrakis(triphenylphosphine)-palladium(0) (0.052 g, 0.05 mmol)was then added and the mixture was heated at reflux for 2 h. The mixturewas then cooled, filtered and the filtrate was concentrated in vacuo togive an aqueous mixture. This mixture was dissolved in EtOAc and waterand the phases were separated. The aqueous solution was extracted withEtOAc. The combined organic solutions were then extracted twice with 2MHCl (40 mL). The aqueous solutions were basified with 2M Na₂CO₃ (50 mL)and extracted with EtOAc (3×40 mL). The combined organic solutions weredried (MgSO₄) and concentrated in vacuo. The residue was dissolved in amixture of CH₂Cl₂ and 2N methanolic ammonia (10:1, 10 mL) and thesolution was filtered through a silica plug. The filtrate wasconcentrated in vacuo to give an oil which subsequently crystallised.Trituration with isohexane and diethyl ether (1:1, 5 mL) and collectionof the resulting solid by filtration gave the title compound (1.093 g,92%) as a yellow crystalline solid; ¹H NMR: 2.23 (2H, dd), 2.27 (3H, s),2.53 (2H, t), 2.93 (2H, d), 3.87 (3H, s), 5.27 (2H, s), 5.42-5.53 (1H,m), 6.65 (1H, s), 7.23 (1H, s); m/z: ES⁺ MH⁺ 264.

Intermediate 4: 4-Bromo-2-methoxy-5-nitroaniline

85% Sulfuric acid was made by adding 98% sulfuric acid (13 mL)cautiously to ice (2g). Guanidine nitrate (1.221 g, 10.00 mmol) wasadded portionwise over a period of 10 minutes to a cooled (0-5° C.)mixture of 4-bromo-2-methoxyaniline (2.020 g, 10 mmol) in 85% sulfuricacid (15.68 mL, 250.00 mmol). The resulting dark blue mixture wasstirred at 0-5° C. for 0.75 h and was then poured very slowly into awell-stirred mixture of 50% aq NaOH (40 mL) and ice (120g). An orangeprecipitate was collected by filtration, washed with water (4×50 mL) andair dried. This material was dissolved into diethyl ether (100 mL) andfiltered through a silica plug. The resulting solution was diluted withisohexane and purified by evaporative crystallisation from diethylether/isohexane to give the title compound (1.821 g, 74%) as an orangecrystalline solid; ¹H NMR: 3.90 (3H, s), 5.52 (2H, s), 7.14 (1H, s),7.32 (1H, s).

Intermediate 5:3-(2-Chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine

K₂CO₃ (10.60 g, 76.68 mmol) was added to a mixture of4-[(E)-2-butoxyethenyl]-2-chloro-5-methylpyrimidine (Intermediate 6,6.95 g, 30.67 mmol) and 1-aminopyridinium iodide (9.19 g, 41.40 mmol) inDMF (40 mL) at r.t. The resulting dark blue suspension was stirred atr.t. for 3 days (became deep red color) and was then heated at 110° C.for 3 h. The mixture was then cooled, diluted with EtOAc (100 mL) plus alittle CH₂Cl₂. This solution was washed with water (100 mL) and theaqueous wash solution was extracted with EtOAc (100 mL). The combinedorganic solutions were washed with water (4×100 mL) and sat. brine (50mL), dried (MgSO₄) and concentrated in vacuo. The residue was dissolvedin THF (100 mL) and filtered through a 30g silica pad. The elutedsolution was concentrated in vacuo and the residue was washed with −70°C. CH₃OH to give the title compound (2.223 g, 30%) as a beigecrystalline solid; ¹H NMR: 2.53 (3H, s), 7.22 (1H, m), 7.64 (1H, m),8.53-8.59 (2H, m), 8.70 (1H, s), 8.90 (1H, d); m/z: ES⁺ MH⁺ 245.

Intermediate 6: 4-[(E)-2-Butoxyethenyl]-2-chloro-5-methylpyrimidine

Diacetoxypalladium (0.482 g, 2.15 mmol) was added in one portion to amixture of 1-(vinyloxy)butane (11.91 mL, 92.02 mmol),2,4-dichloro-5-methylpyrimidine (5 g, 30.67 mmol) and triethylamine(4.51 mL, 32.21 mmol) in degassed polyethylene glycol 200 (25 mL) underN₂. The resulting mixture was stirred at 80° C. for 18 h. The mixturewas then cooled and extracted with diethyl ether (3×75 mL). The combinedorganic solutions were dried (MgSO₄), diluted with heptane (115 mL) andfiltered through a 75g silica plug, eluting with 2:1 diethylether/heptanes, to give the title compound (8.62 g, 124%) as a yellowoil which was used without further purification; ¹H NMR: 0.92 (3H, t),1.35-1.43 (2H, m), 1.60-1.71 (2H, m), 2.17 (3H, d), 4.06 (2H, t), 5.93(1H, d), 7.90 (1H, d), 8.33 (1H, d); m/z: ES⁺ MH⁺ 226.

Intermediate 7:N′-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine

NaOH (2M, 1.488 mL, 2.98 mmol) was added in one portion to a mixture ofN′-{4-[1-(benzenesulfonyl)indol-3-yl]-5-chloropyrimidin-2-yl}-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine(Intermediate 8, 283 mg, 0.47 mmol) in CH₃OH (6 mL) at r.t. under N₂.The resulting solution was stirred at reflux for 0.5h. Dry ice was thenadded and the resulting mixture was concentrated in vacuo. The resultingresidue was triturated with CH₂Cl₂/CH₃OH (4:1, 20 mL), filtered and thefiltrate was concentrated in vacuo to give a residue. Purification byFCC, eluting with 2-10% methanolic ammonia in CH₂Cl₂ gave the titlecompound (102 mg, 47%) as a pale yellow powder; ¹H NMR: 2.30 (3H, s),2.41 (2H, s), 2.60 (2H, t), 3.02 (2H, d), 3.70 (3H, s), 4.27 (2H, s),5.73 (1H, s), 6.65 (1H, s), 7.08 (1H, t), 7.17-7.23 (1H, m), 7.26 (1H,s), 7.48 (1H, d), 8.18 (1H, s), 8.38 (1H, s), 8.41 (1H, d), 8.49 (1H,s), 11.85 (1H, s); m/z: ES⁺ MH⁺ 460.

Intermediate 8:N′-{4-[1-(Benzenesulfonyl)indol-3-yl]-5-chloropyrimidin-2-yl}-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine

A mixture of4-[1-(benzenesulfonyl)indol-3-yl]-5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]pyrimidin-2-amine(Intermediate 9, 349 mg, 0.47 mmol), iron (157 mg, 2.82 mmol) and NH₄Cl(17.60 mg, 0.33 mmol) in ethanol (9 mL) and water (3 mL) was heated atreflux for 1.5h. The mixture was cooled and concentrated in vacuo.CH₂Cl₂ (20 mL) and CH₃OH (2 mL) were then added and the mixture wasstirred for 5 minutes and then filtered. The organic solution was washedwith brine, dried (MgSO₄) and concentrated in vacuo to give the titlecompound (396 mg, 140%) as a green foam which was used without furtherpurification. m/z: ES⁺ MH⁺ 601.

Intermediate 9:4-[1-(Benzenesulfonyl)indol-3-yl]-5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]pyrimidin-2-amine

A mixture of 1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole(Intermediate 10, 384 mg, 0.95 mmol), p-toluene sulphonic acidmonohydrate (271 mg, 1.43 mmol) and 2-smethoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline(Intermediate 3, 250 mg, 0.95 mmol) was heated in 2-pentanol (12 mL) atreflux under N₂ for 24 h. Further p-toluene sulphonic acid monohydrate(0.090 g, 0.48 mmol) was then added and the mixture was heated at refluxfor a further 6h. The mixture was then concentrated in vacuo and theresulting reside was dissolved into a mixture of CH₂Cl₂, CH₃OH and EtOAc(10 mL, 3 mL and 3 mL). This solution was concentrated in vacuo ontosilica. Purification by FCC, eluting with 4-10% CH₃OH in CH₂Cl₂ gave thetitle compound (415 mg, 56%) as a yellow foam; ¹H NMR: 2.29 (1.95H, s),2.52 (0.7H, m), 2.73 (2.6H, s), 3.18 (1.4H, m), 3.57 (2H, s), 3.96 (3H,s), 5.68 (1H, s), 7.00 (1H, s), 7.11 (1.3H, d), 7.26 (1H, m), 7.44 (1H,m), 7.49 (1.3H, d), 7.64 (2H, t), 7.73 (1H, m), 8.01 (1H, d), 8.07-8.15(2H, m), 8.19 (1H, d), 8.64 (2H, d), 8.70 (1H, s), 8.97 (1H, s); (thespectrum seems to appear to show a mixture of rotamers, arising due torestricted rotation of bonds within the molecule) m/z: ES⁺ MH⁺ 631.

Intermediate 10:1-(Benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole

Sodium tert-butoxide (529 mg, 5.50 mmol) was added portionwise over aperiod of 2 minutes to a mixture of3-(2,5-dichloro-pyrimidin-4-yl)-1H-indole (Intermediate 11, 1.321 g, 5.0mmol) and benzenesulfonyl chloride (0.645 mL, 5.00 mmol) in DMF (30 mL)at r.t. under N₂. The resulting solution was stirred at r.t. for 1 h.Further benzenesulfonyl chloride (0.064 mL, 0.50 mmol) and sodiumtert-butoxide (0.053 g, 0.055 mmol) were added and the mixture wasstirred at r.t. for a further 0.25h. The reaction was quenched by theaddition of CH₃OH (6 mL) and neutralised by the addition of solid CO₂pellets until reaching pH=7. The solvent was then removed in vacuo andthe resulting residue was dissolved in CH₂Cl₂ (100 mL). This solutionwas filtered through a 20g silica pad, and the eluted solution wasdiluted with isohexane (50 mL). This solution was concentrated in vacuoto give a volume of 70 mL and was then cooled. A resulting crystallineprecipitate was collected by filtration, washed with isohexane/CH₂Cl₂(4:1, 50 mL) and dried by suction to give the title compound (923 mg,46%) as an off-white crystalline solid, which was used without furtherpurification; ¹H NMR: 7.39-7.53 (2H, m), 7.64 (2H, t), 7.75 (1H, t),8.04 (1H, d), 8.11-8.17 (2H, m), 8.28 (1H, d), 8.79 (1H, s), 9.00 (1H,s); m/z: ES⁺ MH⁺ 404.

Intermediate 11: 3-(2,5-Dichloropyrimidin-4-yl)-1H-indole

CH₃MgBr (3.2M in 2-methyltetrahydrofuran, 3.37 mL, 10.79 mmol) was addeddropwise over 10 minutes to a solution of indole (1.28 g, 10.79 mmol) inTHF (6 mL) at 0° C. The solution was then stirred at 0-2° C. for 0.5h.2,4,5-Trichloropyrimidine (1 g, 5.40 mmol) was then added dropwise,resulting in a yellow solution. The ice bath was removed, then thesolution was stirred at r.t. for 1 h, resulting in a red solution. Themixture was heated to 60° C. and then stirred at 60° C. for 1.5h. Themixture was then cooled to r.t. and acetic acid (634 μL, 11.06 mmol) wasadded dropwise. Water (9.90 mL) and THF (2 mL) were added, then themixture was stirred for 20 minutes at 60° C., resulting in a bi-phasicsolution. The layers were separated and heptane (11 mL) was added to theorganic solution, resulting in the crystallisation of a solid. The solidwas collected by filtration, washed with heptane (2 mL), and dried in avacuum oven to give the title compound (1.015 g, 66%) as a yellow solid;¹H NMR: 7.24-7.32 (2H, m), 7.55-7.58 (1H, m), 8.52-8.55 (1H, m),8.71-8.73 (2H, m), 12.24 (1H, s); m/z: ES⁺ MH⁺ 264, 266.

Intermediate 12:N′-[4-(1H-Indol-3-yl)-5-methylpyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A mixture of4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methylpyrimidin-2-amine(Intermediate 13, 157 mg, 0.33 mmol), iron (111 mg, 1.99 mmol) and NH₄Cl(12.41 mg, 0.23 mmol) was heated in ethanol (6 mL) and water (2 mL) atreflux for 2 h. The mixture was then cooled and concentrated in vacuo togive a thick slurry. CH₂Cl₂ (100 mL) and CH₃OH (10 mL) were then addedand the mixture was stirred for 0.25h, then filtered. The filter cakewas washed with CH₂Cl₂ (50 mL) and CH₃OH (5 mL) and the combined organicsolutions were dried (MgSO₄) and concentrated in vacuo. Purification byFCC, eluting with 1-5% methanolic ammonia in CH₂Cl₂ gave the titlecompound (113 mg, 77%) as a pale yellow dry film; m/z: ES⁺ MH⁺ 444.53.

Intermediate 13:4-(1H-Indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methylpyrimidin-2-amine

A mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline(Intermediate 14, 204 mg, 0.77 mmol), p-toluene sulphonic acidmonohydrate (291 mg, 1.53 mmol) and3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (Intermediate 17, 192 mg,0.77 mmol) were heated at 120° C. in 2-pentanol (15 mL) for 24 h,resulting in a dark brown suspension. The mixture was then concentratedin vacuo and the resulting residue was dissolved in a mixture of CH₂Cl₂and CH₃OH (50 mL and 5 mL) and this solution was concentrated ontosilica in vacuo. Purification by FCC, eluting with 1-5% methanolicammonia in CH₂Cl₂ gave the title compound (157 mg, 43%) as an orangegum; m/z: ES⁺ MH⁺ 474.24.

Intermediate 14: 2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline

tert-ButylN-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]carbamate(Intermediate 15, 1.4 g, 3.82 mmol) was dissolved in CH₂Cl₂ (20 mL) andTFA (5 mL) was then added. The mixture was stirred for 2 h at r.t. andwas then concentrated in vacuo. The resulting residue was dissolved inCH₃OH, absorbed onto an SCX column, washed with CH₃OH and eluted withmethanolic ammonia. The fractions that contained product were combinedand concentrated. Purification by FCC, eluting with 1.5% 7N methanolicammonia in CH₂Cl₂ gave the title compound (0.6 g, 59%) as an orange oilwhich crystallised on standing; ¹H NMR: 2.22 (3H, s), 2.39-2.47 (4H, m),2.87-2.97 (4H, m), 3.88 (3H, s), 4.99 (2H, s), 6.72 (1H, s), 7.20 (1H,s); m/z: ES⁺ MH⁺ 267.5.

Intermediate 15: tert-butylN-[1-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]carbamate

2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrobenzoic acid (Intermediate16, 1.5 g, 5.08 mmol) was suspended in a mixture of t-butanol (20 mL)and DIPEA (1.318 mL, 7.62 mmol) and then diphenylphosphoryl azide (1.642mL, 7.62 mmol) was added. The mixture was then heated at reflux for 2 h.The mixture was then cooled and concentrated in vacuo. The resultingresidue was dissolved in EtOAc, washed with sat. NaHCO₃, dried (Na₂SO₄)and concentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (1.45 g, 78%) as anorange oil which crystallised on standing; ¹H NMR: 1.45 (9H, s), 2.23(3H, s), 2.41-2.49 (4H, m), 2.99-3.07 (4H, m), 3.92 (3H, s), 6.74 (1H,s), 8.24-8.32 (2H, m); m/z: ES⁺ MH⁺ 367.3.

Intermediate 16: 2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrobenzoicacid

1-Methylpiperazine (0.962 mL, 8.67 mmol) was added to a suspension of2-methoxy-4,5-dinitrobenzoic acid (2.0 g, 8.26 mmol) in water (5 mL).The mixture was heated at 50° C. for 1.5 h then 75° C. for 3 h. Afurther 0.5 equivalents of 1-methylpiperazine was added and the mixturewas heated overnight. The mixture was then allowed to cool and stand. Acrystalline solid formed which was collected by filtration, washed withwater and then dried on the filter to give the title compound (1.87 g,77%) as a yellow crystalline solid; ¹H NMR: 2.25 (3H, s), 2.45-2.49 (4H,m), 3.13-3.21 (4H, m), 3.93 (3H, s), 6.63 (1H, s), 8.32 (1H, s); m/z:ES⁺ MH⁺ 296.5.

Intermediate 17: 3-(2-Chloro-5-methylpyrimidin-4-yl)-1H-indole

CH₃MgBr (3.2M in 2-methyltetrahydrofuran, 3.76 mL, 12.02 mmol) was addeddropwise over 10 minutes to a solution of indole (1.42 g, 12.02 mmol) inTHF (4.9 mL) at 0° C. The solution was then stirred at 0-2° C. for 0.5h.A solution of 2,4-dichloro-5-methylpyrimidine (1 g, 6.01 mmol) in THF (3mL) was then added dropwise to the solution. The ice bath was thenremoved, then the solution was stirred at r.t. for 1 h then 60° C. for21 h. While still at 60° C., acetic acid (708 μL, 12.32 mmoles) wasadded dropwise, followed by water (10 mL). The resulting biphasicsuspension was stirred at 60° C. for 0.5h. The resulting solid wascollected by filtration, washed with water (5 mL), and dried in a vacuumoven to give the title compound (805 mg, 50%) as a white solid; ¹H NMR:2.49 (3H, s), 7.20-7.28 (2H, m), 7.52-7.55 (1H, m), 8.20 (1H, d), 8.48(1H, d), 8.51-8.54 (1H, m), 12.10 (1H, s); m/z: ES⁺ MH⁺ 244.

Intermediate 18:N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 19, 145 mg, 0.28 mmol), iron (95 mg, 1.71 mmol) and NH₄Cl(11.4 mg, 0.21 mmol) was heated at reflux in ethanol (6 mL) and water (2mL) for 1.5h. The mixture was then cooled and concentrated in vacuo. Theresulting residue was triturated using 10% CH₃OH in CH₂Cl₂ (15 mL) for15 minutes and the mixture was then filtered. The residues weretriturated again using 10% CH₃OH in CH₂Cl₂ (15 mL) and the mixture wasfiltered. The combined filtrates were washed with brine, dried (Na₂SO₄)and concentrated in vacuo. Purification by FCC, eluting with 2% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (112 mg, 82%) as ayellow gum; ¹H NMR: (CDCl₃) 1.83-1.96 (1H, m), 2.08-2.23 (1H, m), 2.30(6H, s), 2.82-2.92 (1H, m), 2.99-3.13 (2H, m), 3.17-3.28 (2H, m), 3.65(2H, s), 3.84 (3H, s), 6.72 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.52(1H, s), 7.90 (1H, s), 8.36 (1H, s), 8.55-8.60 (1H, m), 8.65 (1H, dd),8.94 (1H, s); m/z: ES⁺ MH⁺ 479.5.

Intermediate 19:5-Chloro-N-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

(3R)—N,N-Dimethylpyrrolidin-3-amine dihydrochloride (90 mg, 0.48 mmol)was added to a suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 200 mg, 0.48 mmol) and DIPEA (0.250 mL, 1.45 mmol) inDMA (3 mL). This mixture was heated at 140° C. in a microwave for 0.5h.The mixture was then diluted with CH₃OH and absorbed onto an SCX column,washed with CH₃OH and eluted with 1:1 methanolic ammonia in CH₂Cl₂.Fractions containing the product were combined and concentrated invacuo. Purification by FCC, eluting with 1.5% 7N methanolic ammonia inCH₂Cl₂ gave the title compound (149 mg, 61%) as an orange foam; ¹H NMR:1.76-1.89 (1H, m), 2.14-2.25 (7H, m), 2.69-2.84 (1H, m), 3.12-3.27 (3H,m), 3.41-3.53 (1H, m), 3.89 (3H, s), 6.56 (1H, s), 7.13 (1H, td),7.26-7.38 (1H, m), 8.06 (1H, s), 8.40-8.43 (2H, m), 8.73 (1H, s), 8.85(1H, d), 8.95 (1H, s); m/z: ES⁺ MH⁺ 509.5.

Intermediate 20:5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-amine

A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine(Intermediate 21, 1.4 g, 5.28 mmol), 4-fluoro-2-methoxy-5-nitroaniline(Intermediate 23, 1.032 g, 5.55 mmol) and p-toluenesulfonic acidmonohydrate (1.105 g, 5.81 mmol) was heated at 125° C. in 2-pentanol (40mL) for 18 h. The mixture was then cooled and a solid was collected byfiltration. The solid was washed with CH₃OH and diethyl ether, and wasthen dried on the filter to give the title compound (1.73 g, 79%) as ayellow powder; ¹H NMR: 3.98 (3H, s), 7.16 (1H, td), 7.33-7.48 (2H, m),8.49 (1H, d), 8.53 (1H, d), 8.66 (1H, d), 8.86 (1H, d), 8.90 (1H, s),8.96 (1H, s).

Intermediate 21: 3-(2,5-Dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine

K₂CO₃ (20.82 g, 150.65 mmol) and KOH (16.91 g, 301.31 mmol) were addedin one portion to a mixture of(E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine (Intermediate 22, 74.46 g,301.31 mmol) and 1-aminopyridinium iodide (66.9 g, 301.31 mmol) in DMSO(1.415 L) at r.t. The mixture was stirred at r.t. for 1.5 h and then at90° C. for 4 h. After cooling, the mixture was diluted with water (5 L)and stirred for 0.5h. The resulting solid was collected by filtrationand washed with water (5 L). Purification by FCC, eluting with 0-20%EtOAc in CH₂Cl₂ gave the title compound (16.2 g, 20%) as a cream solidafter trituration with diethyl ether; ¹H NMR: 7.29 (1H, td), 7.74 (1H,ddd), 8.58 (1H, dt), 8.82 (1H, s), 8.98 (1H, dt), 9.10 (1H, s). m/z:ES⁺, MH⁺ 264.89.

Intermediate 22: 4-[(E)-2-Butoxyethenyl]-2,5-dichloropyrimidine

Degassed 1,4-dioxane (600 mL) was added to palladium(II) acetate (4.80g, 21.37 mmol) under N₂. n-Butyl vinyl ether (275 mL, 2.137 mol),2,4,5-trichloropyrimidine (200 g, 1.069 mol) and DIPEA (194 mL, 1.122mol) were then added. The mixture was heated to 80° C. for 22.5 h andthen cooled to 30° C. Palladium acetate (2.40 g, 10.68 mmol), n-butylvinyl ether (138 mL, 1.068 mol) and DIPEA (97 mL, 561 mmol) were thenadded. The mixture was then heated to 80° C. for 4 h and then allowed tocool to r.t. overnight. The mixture was then added to water (2 L), andthen sat. brine (2 L) was added. The phases were separated and theaqueous solution was extracted with methyl-tert-butylether (2×1 L). Thecombined organic solutions were washed with water resulting in anemulsion which would not separate. Everything was filtered and the twophases were then separated. The organic solution was dried (MgSO₄) andconcentrated to give a brown oil (240g). This material is was split intotwo batches and each purified by FCC, eluting with 0-100% heptane inCH₂Cl₂ to give the title compound (130g, 49%) as a yellow oil; ¹H NMR:0.89-0.97 (3H, t), 1.33-1.45 (2H, m), 1.62-1.72 (2H, m), 4.13 (2H, t),6.08 (1H, d), 8.06 (1H, d), 8.64 (1H, s); m/z: ES⁺ MH⁺ 247.41.

Intermediate 23: 4-Fluoro-2-methoxy-5-nitroaniline

4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise toconcentrated H₂SO₄ (15 mL) which was cooled in a ice/water bath, andwhere the temperature was kept below 15° C. during the addition. Themixture was stirred until all the solid that formed had dissolved. KNO₃(0.815 mL, 17.00 mmol) was added portionwise such that the temperaturewas maintained below 10° C. The mixture was stirred overnight and thenpoured onto ice/water. The mixture was basified with concentrated NH₄OH.The resulting solid was filtered off and then dissolved in CH₂Cl₂,washed with water, dried (Na₂SO₄) and concentrated onto silica.Purification by FCC, eluting with 50-0% heptane in CH₂Cl₂ gave the titlecompound (2.450g, 77%) as a yellow crystalline solid; ¹H NMR: 3.91 (3H,s), 5.21 (2H, s), 7.03 (1H, d), 7.35 (1H, d); m/z: ES⁺ MH⁺ 187.4.

Intermediate 24:N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 25, 265 mg, 0.54 mmol), iron (179 mg, 3.21 mmol) and NH₄Cl(20.05 mg, 0.37 mmol) was heated at reflux in ethanol (6 mL) and water(2 mL) for 1 h. The crude product was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M methanolic ammonia and appropriate fractions wereconcentrated in vacuo to give the title compound (235 mg, 94%) as ayellow solid which was used without further purification; ¹H NMR: 2.13(6H, s), 3.07 (1H, s), 3.50 (2H, t), 3.66 (3H, s), 4.00 (3H, t), 4.05(2H, s), 6.28 (1H, s), 6.79 (1H, s), 7.10 (1H, t), 7.3-7.39 (1H, m),8.33 (1H, s), 8.37 (1H, s), 8.80 (1H, d), 8.93 (1H, s); m/z: ES⁺ MH⁺465.25.

Intermediate 25:5-Chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

DIPEA (0.341 mL, 1.96 mmol) was added to a mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 20, 254 mg, 0.61 mmol) and N,N-dimethylazetidin-3-aminedihydrochloride (Intermediate 26, 106 mg, 0.61 mmol) in DMA (4 mL) andthe mixture was heated to 100° C. for 0.5h. FurtherN,N-dimethylazetidin-3-amine (35 mg, 0.19 mmol) was then added and themixture was heated at 100° C. for a further 2h and was then left at r.t.overnight. The mixture was purified directly by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M methanolic ammonia and was concentrated in vacuoonto silica. Purification by FCC, eluting with 0-4% 7N methanolicammonia in CH₂Cl₂ gave the title compound (310 mg, 102%) as an orangesolid, which was used without further purification; ¹H NMR: 2.14 (6H,s), 3.08-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.02-4.11 (2H, m),6.28 (1H, s), 7.12 (1H, td), 7.30-7.39 (1H, m), 8.12 (1H, s), 8.37 (1H,br s), 8.42 (1H, s), 8.68 (1H, s), 8.83 (1H, d), 8.94 (1H, d); m/z: ES⁺MH⁺ 495.56.

Intermediate 26: N,N-Dimethylazetidin-3-amine—hydrochloride salt

HCl in diethyl ether (200 mL) was slowly added to a solution oftert-butyl 3-dimethyl-aminoazetidine-1-carboxylate (Intermediate 27,62g, 0.31 mol) in diethyl ether (100 mL) and the mixture was stirred for40 mins at r.t. The mixture was then concentrated in vacuo and theresulting solid was washed with diethyl ether to give the title salt(50g, 119%) as a white solid, which was used without furtherpurification; ¹H NMR: 2.66 (6H, s), 4.00-4.05 (2H, m), 4.24-4.28 (m,1H), 4.34-4.38 (m, 2H).

Intermediate 27: tert-butyl 3-dimethylaminoazetidine-1-carboxylate

To a solution of N,N-dimethylazetidin-3-amine (Intermediate 28, 100g,1.0 mol) and triethylamine (487 mL, 3.5 mol) in CH₂Cl₂ (500 mL) wasadded tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (326 g, 1.5mol) at 0° C. The mixture was then stirred at r.t. for 5 h. The mixturewas then washed with water (4×500 mL) and the organic solution weredried (Na₂SO₄) and concentrated in vacuo. Purification by FCC gave thetitle compound (62g, 31%).

Intermediate 28: N,N-Dimethylazetidin-3-amine

1-Chloroethyl carbonochloridate (118 g, 0.83 mol) was added to asolution of 1-benzhydryl-N,N-dimethylazetidin-3-amine (Intermediate 29,200g, 0.75 mol) in dichloroethane (1 L) and the mixture was refluxed at100° C. for 2 h. The mixture was then concentrated in vacuo and theresulting residue was dissolved in CH₃OH (1 L) and this mixture wasrefluxed at 90° C. for 2 h. The mixture was then concentrated to givethe title compound which was used in next step without furtherpurification.

Intermediate 29: 1-Benzhydryl-N,N-dimethylazetidin-3-amine

Aqueous dimethylamine (1 L, 33%) was added to a solution of(1-benzhydrylazetidin-3-yl)methanesulfonate (Intermediate 30, 260g, 0.82mol) in CH₃CN (1 L) and the mixture was refluxed at 100° C. overnight.The mixture was then cooled and the solvent was removed in vacuo. Themixture was partitioned between water (300 mL) and CH₂Cl₂ (300 mL) andthe layers were separated. The aqueous phase was extracted with CH₂Cl₂(3×500 mL). The combined organic solutions were dried (Na₂SO₄) andconcentrated in vacuo. Purification by FCC gave the title compound(200g, 92%) as a brown solid.

Intermediate 30: (1-Benzhydrylazetidin-3-yl)methanesulfonate

A solution of methanesulfonyl chloride (115 g, 1.01 mol) in CH₂Cl₂ (500mL) was added dropwise to a solution of 1-benzhydrylazetidin-3-ol(Intermediate 31, 200g, 0.84 mol) and triethylamine (119 g, 1.17 mmol)in CH₂Cl₂ (2 L) at 0° C., and the mixture was stirred at 0° C. for 1 h.The reaction was quenched by the addition of aqueous NaHCO₃. The phaseswere separated and the aqueous solution was extracted with CH₂Cl₂ (3×500mL). The combined organic solutions were dried (Na₂SO₄) and concentratedin vacuo to give the title compound (260g, 98%) as a white solid.

Intermediate 31: 1-Benzhydrylazetidin-3-ol

DIPEA (129 g, 1 mol) was added to a solution of1-(benzhydrylamino)-3-chloropropan-2-s of (Intermediate 32, 276g, 1 mol)in ethanol (2 L) at 0° C., then the mixture was refluxed at 90° C.overnight. The mixture was then concentrated in vacuo to give the titlecompound (179g, 75%) which could be re-crystallized from acetone andpetroleum ether.

Intermediate 32: 1-(Benzhydrylamino)-3-chloropropan-2-ol

2-(Chloromethyl)oxirane (92 g, 1 mol) was added dropwise to a solutionof diphenyl-methanamine (183 g, 1 mol) in CH₃OH (1 L) at 0° C. then themixture was stirred at r.t. overnight. The mixture was then concentratedin vacuo to give the title compound (201g, 73%) which was used in nextstep without further purification.

Intermediate 33:N⁴-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

A solution of NH₄Cl (45 mg, 0.85 mmol) in water (10 mL) was added in oneportion to a stirred mixture ofN-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine(Intermediate 34, 600 mg, 1.21 mmol) and iron (405 mg, 7.24 mmol) inethanol (30 mL). The resulting mixture was stirred at 105° C. for 3 h.The mixture was then concentrated in vacuo and the resulting residue wasmixed with DMF (10 mL) and purified by ion exchange chromatography,using an SCX column. The desired product was eluted from the columnusing 0.35M methanolic ammonia in CH₂Cl₂ and pure fractions wereconcentrated in vacuo to give the title compound (530 mg, 94%) as abrown gum; ¹H NMR: 2.16 (6H, d), 2.38 (2H, t), 2.66 (3H, d), 2.92 (2H,t), 3.66 (3H, s), 4.60 (2H, s), 6.78 (1H, s), 6.92 (1H, s), 7.12 (1H,t), 7.27-7.4 (1H, m), 8.38 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.83(1H, d), 8.95 (1H, s); m/z: ES⁺ MH⁺ 467.

Intermediate 34:N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine

N,N,N′-Trimethylethylenediamine (0.188 mL, 1.45 mmol) was added to amixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 500 mg, 1.21 mmol) and DIPEA (0.250 mL, 1.45 mmol) inDMA (5 mL) and the mixture was heated at 140° C. in a microwave for 0.5h. The mixture was then diluted with CH₃OH and absorbed onto an SCXcolumn. The column was washed with CH₃OH and eluted with 1:1 methanolicammonia in CH₂Cl₂. Appropriate fractions were concentrated in vacuo togive the title compound (624 mg, 104%) as an orange solid, which wasused without further purification; ¹H NMR: 2.17 (6H, d), 2.89 (3H, d),3.87-3.93 (3H, m), 6.84 (1H, s), 7.14 (1H, td), 7.31-7.38 (1H, m), 8.15(1H, s), 8.39 (1H, d), 8.44 (1H, d), 8.69 (1H, s), 8.85 (1H, d), 8.95(1H, s); m/z: ES⁺ MH⁺ 497.

Intermediate 35:4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

A mixture ofN-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 36, 155 mg, 0.30 mmol), iron (100 mg, 1.79 mmol) and NH₄Cl(11.2 mg, 0.21 mmol) in ethanol (12 mL) and water (4 mL) was heated atreflux for 2 h. The mixture was then cooled and filtered though decalite(a type of diatomaceous earth) and the filtrate was concentrated invacuo to provide a brown gum. Purification by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (105 mg, 72%) as agum; ¹H NMR: (CDCl₃) 1.76-1.80 (1H, m), 2.03-2.20 (2H, m), 2.28 (3H, s),2.48 (1H, dd), 2.59-2.63 (2H, m), 2.76-2.98 (2H, m), 3.46 (1H, dt), 3.78(2H, s), 3.84 (3H, s), 4.07-4.10 (1H, m), 6.73 (1H, s), 6.94 (1H, td),7.36 (1H, ddd), 7.51 (1H, s), 7.86 (1H, s), 8.35 (1H, s), 8.54 (1H, d),8.65 (1H, d), 8.93 (1H, s); m/z: ES⁺ MH⁺ 491.29.

Intermediate 36:N-{4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]-pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine

(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,2-c]pyrrole(Intermediate 37, 91 mg, 0.72 mmol) was added to a mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.334 mL, 1.93 mmol) in2,2,2-trifluoroethanol (3 mL) and the mixture was heated at 140° C. in amicrowave for 0.5h. The mixture was then absorbed onto silica.Purification by FCC, eluting with 2% 7N methnaolic ammonia in CH₂Cl₂gave material that was concentrated in vacuo and dissolved in CH₃OH. Theresulting solution was absorbed onto an SCX column and the column waswashed with CH₃OH then eluted with 7N methanolic ammonia. Appropriatefractions were concentrated in vacuo to give the title compound (155 mg,49%) as a orange/red gummy solid; ¹H NMR: (CDCl₃) 1.89 (1H, dd),2.04-2.19 (1H, m), 2.24 (3H, s), 2.30-2.39 (1H, m), 2.40-2.57 (2H, m),2.68 (1H, t), 2.98-3.11 (1H, m), 3.23 (1H, t), 3.51-3.63 (1H, m), 3.97(3H, s), 4.36-4.48 (1H, m), 6.46 (1H, s), 6.90-7.02 (1H, m), 7.31-7.43(2H, m), 8.38 (1H, s), 8.48 (1H, dd), 8.53-8.57 (1H, m), 8.82 (1H, s),8.93 (1H, s); m/z: ES⁺ MH⁺ 521.45.

Intermediate 37:(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]-pyrrole

Palladium on carbon (10g) was added to a solution of(3aR,6aR)-5-methyl-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrole(Intermediate 38, 20g, 0.087 mol) in ethanol (500 mL) under N₂. Theresulting mixture was hydrogenated at 70° C./45 psi for 24 h. Themixture was then filtered and the filtrate was concentrated in vacuo togive the title compound as a (10.9 g, 99%) solid; ¹H NMR: 1.59-1.66 (1H,m), 1.86-1.95 (1H, m), 2.18 (s, 3H), 2.28-2.34 (2H, m), 2.46-2.47 (1H,m), 2.73 (2H, d), 3.00 (2H, m), 3.90 (2H, m).

Intermediate 38:(3aR,6aR)-5-Methyl-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrole

37% aqueous formaldehyde (1.6 L) was added to a solution of(3aR,6aR)-1-[(1R)-1-phenylethyl]-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,2-c]pyrrole(Intermediate 39, 108g, 0.5 mol) in HCOOH (800 mL) at r.t., then themixture was stirred at 70-80° C. for 2 h. The mixture was then cooled to0° C. and basified with solid NaOH to pH-13. This mixture was thenextracted with CH₂Cl₂ (2×2 L). The combined organic solutions wereconcentrated in vacuo. Purification by FCC, eluting with 2:1 to 1:10hexanes/EtOAc, gave the title compound (80g, 70%) as red oil; ¹H NMR:(CDCl₃) 1.36 (3H, d), 1.65 (1H, m), 1.85 (1H, m), 2.22 (3H, m), 2.32(3H, s), 2.54 (1H, m), 2.68 (2H, m), 2.83 (1H, m), 3.10 (1H, m), 3.40(1H, m), 7.21-7.33 (5H, m).

Intermediate 39:(3aR,6aR)-1-[(1R)-1-phenylethyl]-3,3a,4,5,6,6a-hexahydro-21−/−pyrrolo[3,2-c]pyrrole

A solution of ethyl(3aR,6aR)-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]-pyrrole-5-carboxylate(Intermediate 40, 300g, 1.04 mol) in concentrated HCl (4 L, 37%) wasrefluxed overnight. The mixture was then cooled to 0° C. and extractedwith by CH₂Cl₂ (1 L×2). The aqueous solution was adjusted to pH=12-13using NaOH (solid). The combined organic solutions were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to give the titlecompound (150g, 67%) as dark oil which was used in the next step withoutfurther purification.

Intermediate 40: Ethyl(3aR,6aR)-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,2-c]pyrrole-5-carboxylate

A mixture of ethyl N-(2-oxoethyl)-N-prop-2-enylcarbamate (Intermediate41, 466g, 2.7 mol) and 2-{[(1R)-1-phenylethyl]amino}acetic acid(Intermediate 43A, 490g, 2.7 mol) in toluene (4 L) was refluxedovernight. The resulting mixture was filtered and the filtrate wasconcentrated in vacuo. Purification by FCC, eluting with 10:1petrol-EtOAc, gave the title compound (300g, 38%) as red oil; ¹H NMR:(CDCl₃) 1.10-1.40 (8H, m), 1.55 (1H, m), 1.90 (1H, m), 2.45 (1H, m),2.77 (1H, m), 3.20-3.65 (5H, m), 4.10-4.20 (2H, m), 7.25-7.38 (5H, m).

Intermediate 41: Ethyl N-(2-oxoethyl)-N-prop-2-enylcarbamate

A solution of ethyl N-(2,2-dimethoxyethyl)-N-prop-2-enylcarbamate(Intermediate 42, 1218g, 2.79 mol) in HCOOH (4.2 L) was refluxed for0.5h. Then crushed ice was added to quench the reaction, the mixture wasextracted with CH₂Cl₂ (2 L×3). The combined organic solutions werewashed with sat. NaHCO₃ (3 L), dried (Na₂SO₄) and concentrated in vacuoto give the title compound (480g, 50%) as yellow oil; ¹H NMR: (CDCl₃)1.15-1.32 (3H, m), 3.89-4.00 (4H, m), 4.07-4.16 (2H, m), 5.10 (2H, m),5.73 (1H, m), 9.53 (1H, s).

Intermediate 42: Ethyl N-(2,2-dimethoxyethyl)-N-prop-2-enylcarbamate

Crushed KOH (1417 g, 25.3 mol) was added in portions to a solution ofethyl N-(2,2-dimeth-oxyethyl)carbamate (Intermediate 43, 1123g, 6.3 mol)in toluene (5 L). Benzyltriethyl-ammonium chloride (14.0 g, 0.06 mol)and allyl bromide (532 g, 4.4 mol) were then added at r.t. The mixturewas then stirred at r.t. overnight. The mixture was then filtered andthe reaction mixture was washed with brine (2 L), dried (Na₂SO₄) andconcentrated in vacuo to give the title compound (1218g, 89%) as ayellow oil; ¹H NMR: (CDCl₃) 1.23 (3H, s), 3.28 (2H, s), 3.36 (6H, s),3.92 (2H, d), 4.12 (2H, s), 4.47 (1H, d), 5.08 (2H, d), 5.73 (1H, s).

Intermediate 43: Ethyl N-(2,2-dimethoxyethyl)carbamate

A solution of NaOH (578.4 g, 14.46 mol) in H₂O (2 L) was added to asolution of 2,2-dimethoxyethanamine (800 g, 7.6 mol) in toluene (2 L)and the resulting mixture was cooled to 0° C. using an ice bath. Ethylchloroformate (825 g, 7.6 mol) was added dropwise while keeping thetemperature near 10° C. The mixture was then stirred at r.t. overnight.The phases were then separated and the aqueous solution was saturatedwith solid NaCl. This solution was then extracted with toluene (1.25L×3). The combined organic solutions were dried (Na₂SO₄) andconcentrated in vacuo to give the title compound (1.123 kg, 83%) ascolorless oil; ¹H NMR: (CDCl₃) 1.17 (3H, t), 3.14 (2H, s), 3.32 (6H, s),4.02-4.07 (2H, m), 4.30 (1H, t).

Intermediate 43A: 2-{[(1R)-1-Phenylethyl]amino}acetic acid

Methyl 2-{[(1R)-1-phenylethyl]amino}acetate (Intermediate 44, 587.0 g,3.0 mol) was refluxed in aqueous KOH (3.36 g, 0.06 mol dissolved in 2.5L water) overnight. The phases were then separated and the aqueoussolution was washed with EtOAc (3×1 L). The combined organic solutionswere concentrated in vacuo to give the title compound (490g, 90%) aswhite solid; ¹H NMR: 1.48 (3H, d), 2.89 (1H, d), 3.00 (1H, d), 4.20 (1H,m), 7.37-7.43 (5H, m).

Intermediate 44: Methyl 2-{[(1R)-1-phenylethyl]amino}acetate

Methyl 2-bromoacetate (621 g, 4.1 mol) was added dropwise to a mixtureof (1R)-1-phenylethanamine (410 g, 3.4 mol) and triethylamine (377 g,3.7 mol) in EtOAc (4.5 L) at r.t. The mixture was then stirred at 50-60°C. overnight then cooled to r.t. The mixture was then washed with water(800 mL) and brine (100 mL), dried (Na₂SO₄) and concentrated in vacuo togive the title compound (587g, 90%) as yellow oil; ¹H NMR: (CDCl₃) 1.29(3H, d), 3.13-3.24 (2H, m), 3.60 (3H, s), 3.68-3.71 (1H, m), 7.13-7.26(5H, m).

Intermediate 45:N′-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)benzene-1,3-diamine

A mixture of5-chloro-N-[2-methoxy-4-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 46, 95 mg, 0.18 mmol), iron (61 mg, 1.09 mmol) and NH₄Cl(7.32 mg, 0.14 mmol) was heated at reflux in ethanol (10.5 mL) and water(3.5 mL) for 2 h. The mixture was cooled and filtered throughdiatomaceous earth (Celite™). The filtrate was concentrated in vacuo andthe residue was dissolved in CH₂Cl₂. This solution was washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. Purification by FCC,eluting with 2-6% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (30 mg, 34%) as a brown gum; m/z: ES⁺ MH⁺ 491.5.

Intermediate 46:5-Chloro-N-[2-methoxy-4-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

A mixture of 5-methyl-2,5-diazaspiro[3.4]octane dihydrochloride salt(Intermediate 47, 400 mg) in CH₃OH/water was absorbed onto an SCXcolumn. The column was washed with CH₃OH and eluted with methanolicammonia. The fractions containing product were combined and concentrated(caution: product is volatile). A mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 250 mg, 0.60 mmol), 5-methyl-2,5-diazaspiro[3.4]octane(91 mg, 0.72 mmol) and DIPEA (0.365 mL, 2.11 mmol) in DMA (3 mL) washeated at 140° C. for 0.5h in a microwave. The mixture was then dilutedwith CH₃OH and absorbed onto an SCX column. The column was washed withCH₃OH and eluted with 1:1 methanolic ammonia in CH₂Cl₂. Fractionscontaining the product were combined and concentrated to provide asolid. This solid was suspended in CH₃OH, filtered, washed with diethylether and dried to give the title compound (267 mg, 85%) as a red solid;¹H NMR: 1.63-1.78 (2H, m), 2-2.12 (2H, m), 2.41 (3H, s), 2.69 (2H, t),3.77 (2H, d), 3.90 (3H, s), 4.13 (2H, d), 6.30 (1H, s), 7.14 (1H, td),7.34 (1H, t), 8.12 (1H, s), 8.41-8.46 (2H, m), 8.74 (1H, s), 8.86 (1H,d), 8.96 (1H, s); m/z: ES⁺ MH⁺ 521.46.

Intermediate 47: 5-Methyl-2,5-diazaspiro[3.4]octane dihydrochloride salt

A 4M solution of HCl in EtOAc (120 mL) was prepared by adding acetylchloride (34 mL) to a solution of ethanol (28 mL) and EtOAc (58 mL).This solution was then added to a mixture of2-benzyl-5-methyl-2,5-diazaspiro[3.4]octane (Intermediate 48, 48g,221.89 mmol) and Pd(OH)₂ (34g, 20% on carbon) in 1.5 L of CH₃OH. Themixture was then stirred at 30° C. under 55 psi of H₂ for 24 h. Themixture was then filtered and the filtrate was concentrated in vacuo togive the title salt (42.7 g, 96%) as yellow oil; ¹H NMR: (d⁴-methanol)1.98-2.11 (2H, m), 2.53 (2H, t), 3.02 (3H, s), 3.38 (2H, t), 4.17 (2H,d), 4.68 (2H, d).

Intermediate 48: 2-Benzyl-5-methyl-2,5-diazaspiro[3.4]octane

Paraformaldehyde (70.91 g, 787 mmol) and triethylamine (119.5 g, 1.18mol) were added to a mixture of 2-benzyl-2,5-diazaspiro[3.4]octanedihydrochloride (Intermediate 49, 65 g, 236.2 mmol) in1,2-dichloroethane (700 mL) and the mixture was stirred for 1 h at 10°C. Sodium triacetoxyborohydride (110.8 g, 1.18 mol) was then added andthe mixture was stirred for 12 h at 15° C. The mixture was then filteredand the filter cake was washed with CH₂Cl₂ (3×500 mL). The combinedorganic solutions were washed with brine (500 mL), dried (MgSO₄) andconcentrated in vacuo to give the title compound (51.1 g, 94%) as yellowoil; ¹H NMR: (300 MHz, CDCl₃) 1.75 (2H, m), 2.16 (2H, m), 2.49 (3H, s),2.64 (2H, d), 3.10 (2H, d), 3.28 (2H, d), 3.66 (2H, s), 7.22-7.62 (5H,m).

Intermediate 49: 2-Benzyl-2,5-diazaspiro[3.4]octane dihydrochloride

A 4M solution of HCl in EtOAc (2 L) was added to a solution oftert-butyl 2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate(Intermediate 50, 195g, 644.8 mmol) in EtOAc (0.5 L) and the mixture wasstirred for 12 h. The resulting solid was collected by filtration andwashed with tert-butylmethyl ether (2 L) to give the title salt (170g,96%) as white solid; ¹H NMR: (d⁴-methanol) 2.04-2.11 (2H, m), 2.41 (2H,t), 3.39 (2H, t), 4.33 (2H, s), 4.81-4.88 (2H, m), 7.49-7.58 (5H, m).

Intermediate 50: tent-Butyl2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate

A solution of CBr₄ (369.5 g, 1.115 mol) in 1 L of CH₂Cl₂ was addeddropwise to a solution of tert-butyl2-[(benzylamino)methyl]-2-(hydroxymethyl)pyrrolidine-1-carboxylate(Intermediate 51, 178.5 g, 555 mmol) and triphenylphosphine (292 g,1.115 mol) in CH₂Cl₂ (1.8 L) at 0° C. The resulting mixture was stirredat r.t. for 2 h then concentrated in vacuo. The residue was suspended ina mixture of CH₃CN (2 L) and triethylamine (563.5 g, 5.57 mol) andrefluxed at 80° C. for 24 h. The mixture was then concentrated in vacuo.Purification by FCC, eluting with 1:1 petrol-EtOAc gave the titlecompound (97.5 g, 58%) as yellow oil; ¹H NMR: (300 MHz, CDCl₃) 1.47-1.72(11H, m), 2.30 (2H, m), 3.19 (2H, d), 3.31-3.47 (2H, m), 3.82-4.12 (4H,m), 7.22-7.28 (5H, m).

Intermediate 51:2-[(Benzylamino)methyl]-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Borane-dimethylsulfide (170 mL, 1.7 mol) was added to a solution oftert-butyl 2-benzyl-3-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate(Intermediate 52, 179g, 567 mmol) in 1.8 L of THF and the mixture wasrefluxed at 80° C. for 12 h. The reaction was then quenched by theaddition of CH₃OH (1 L), and water (1.5 L). The phases were thenseparated and the aqueous solution was extracted with EtOAc (3×1 L),then the combined organic solutions were washed with brine (3×1 L),dried (MgSO₄) and concentrated in vacuo to the title compound (119g,66%) as yellow oil; ¹H NMR: (CDCl₃) 1.47 (10H, m), 1.55-1.78 (3H, m),2.06 (1H, m), 2.57 (2H, d), 3.17 (1H, m), 3.35 (2H, m), 3.37 (1H, m),3.75-3.87 (3H, m), 7.23-7.40 (5H, m).

Intermediate 52: tent-Butyl2-benzyl-3-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate

n-Butyllithum (268.7 mL, 0.672 mmol, 2.5 M in hexane) was added to asolution of diisopropylamine (70 g, 691.7 mmol) at −70° C. in dry THF(1.5 L) under N₂ then the mixture was stirred for 1 h at −70° C. Asolution of 1-tert-butyl 2-methylpyrrolidine-1,2-s dicarboxylate(Intermediate 53, 140g, 610 mmol) in anhydrous THF (360 mL) was thenadded dropwise at −70° C. After stirring at −70° C. for 1 h, a solutionof 2-(benzylamino)-acetonitrile (Intermediate 54, 45.9 g, 305.7 mmol) inanhydrous THF (360 mL) was added dropwise at −70° C. over a period of 1h. Then the resulting mixture was warmed to r.t. then stirred for 12 h.Sat. NH₄Cl (1.5 L) was then added and the resulting phases wereseparated. The aqueous solution was extracted with EtOAc (3×1 L). Thecombined organic solutions were washed with brine (3×1 L), dried (MgSO₄)and concentrated in vacuo. Purification by FCC, eluting with 2:1petroleum ether/EtOAc gave the title compound (75.5 g, 76%) as yellowoil; ¹H NMR: (CDCl₃) 1.44 (9H, m), 1.77 (1H, m), 1.93 (1H, m), 2.04 (1H,m), 2.37 (1H, m), 3.00 (1H, m), 3.40-3.67 (3H, m), 3.95 (1H, m),4.25-4.89 (1H, m), 7.21-7.36 (5H, m).

Intermediate 53: 1-tent-Butyl 2-methylpyrrolidine-1,2-dicarboxylate

K₂CO₃ (1.1 kg, 8.0 mol) and CH₃I (659 g, 4.65 mol) was added to asolution of 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylicacid (500 g, 2.32 mol) in DMF (2.5 L) at r.t. and the mixture wasstirred for 12 h, then filtered. The filtrate was concentrated in vacuo.The residue was dissolved in EtOAc (2 L) and washed with water (2×1 L),brine (1 L), dried (MgSO₄) and concentrated in vacuo to give the titlecompound (417.8 g, 96%) as yellow oil; ¹H NMR: (CDCl₃) 1.37 (9H, m),1.72-1.84 (3H, m), 2.15 (1H, m), 3.26-3.51 (2H, m), 3.65 (3H, s), 4.17(1H, m).

Intermediate 54: 2-(Benzylamino)acetonitrile

A solution of the ClCH₂CN (316 g, 4.19 mol) in EtOAc (200 mL) was addeddropwise to benzylamine (900 g, 8.40 mol) while the mixture wasvigorously stirred. The mixture was warmed gently to 45° C. for 0.5 hand a white precipitate was removed by filtration. The filtrate wasconcentrated in vacuo to give the title compound (606g, 99%) as yellowoil; ¹H NMR: (CDCl₃) 3.56 (2H, s), 3.94 (2H, s), 7.28-7.40 (5H, m).

Intermediate 55:N′-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine

A mixture of5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 56, 470 mg, 0.96 mmol), iron (320 mg, 5.73 mmol) and NH₄Cl(35.8 mg, 0.67 mmol) in ethanol (19 mL) and water (6.33 mL) was heatedat reflux for 4 h. Then the mixture was cooled and concentrated in vacuoto give a thick slurry which was triturated with 10% CH₃OH in CH₂Cl₂ (50mL) for 15 minutes. The mixture was then filtered and a small amount ofsat. NaHCO₃ was added to the filtrate. The resulting phases wereseparated and the aqueous solution was extracted with 10% CH₃OH inCH₂Cl₂ (50 mL). The combined organic solutions were washed with brine,dried (Na₂SO₄) and concentrated in vacuo. Purification by FCC, elutingwith 2.5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (387mg, 88%) as a yellow foam; ¹H NMR: 2.31 (3H, s), 2.38-2.44 (2H, m), 2.61(2H, t), 3.02 (2H, dd), 3.68 (3H, s), 4.33 (2H, d), 5.72-5.76 (1H, m),6.66 (1H, s), 7.08 (1H, s), 7.14 (1H, td), 7.35-7.43 (1H, m), 8.41 (1H,s), 8.44 (1H, s), 8.49 (1H, d), 8.84 (1H, d), 8.96 (1H, s); m/z: ES⁺ MH⁺462.5.

Intermediate 56:5-Chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine(Intermediate 21, 575 mg, 1.86 mmol) and2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline(Intermediate 3, 490 mg, 1.86 mmol) was stirred in THF (30 mL) andcooled in an ice/water bath. Lithium bis(trimethylsilyl)amide (4.10 mL,4.10 mmol, 1M in THF) was then added dropwise and the mixture wasstirred for 1 h. CH₃OH was added and the mixture was concentrated invacuo. The crude material was suspended in CH₃OH and the mixture wasfiltered. The collected solid was washed with CH₃OH and diethyl etherand dried on the filter to give the title compound (660 mg, 72%) as ayellow powder; ¹H NMR: 2.29 (3H, s), 2.30-2.38 (2H, m), 2.58 (2H, t),2.97 (2H, dd), 3.96 (3H, s), 5.60-5.68 (1H, m), 7.00 (1H, s), 7.16 (1H,td), 7.36-7.45 (1H, m), 8.49-8.56 (3H, m), 8.87 (1H, d), 8.90 (1H, s),8.97 (1H, s); m/z: ES⁺ MH⁺ 492.4.

Intermediate 57:2-(4-{2-Amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-N,N-dimethylacetamide

A mixture of2-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-N,N-dimethylacetamide(Intermediate 58, 0.234 g, 0.41 mmol), iron (0.139 g, 2.48 mmol) andNH₄Cl (0.015 g, 0.29 mmol) in ethanol (10 mL) and water (3.33 mL) washeated at reflux for 4 h. The mixture was then allowed to cool to r.t.,was filtered and the filtrate concentrated in vacuo. Purification by ionexchange chromatography, using an SCX column and eluting with 1Mmethanolic ammonia, gave a brown gum after concentration of appropriatefractions. Further purification by FCC, eluting with 0-5% CH₃OH inCH₂Cl₂ gave the title compound (0.19 g, 86%) as a yellow foam; ¹H NMR:(CDCl₃) 2.72 (4H, s), 2.93-3.01 (7H, m), 3.13 (3H, s), 3.27 (2H, s),3.65-3.83 (2H, m), 3.84 (3H, s), 6.71 (1H, s), 6.96 (1H, td), 7.38 (1H,ddd), 7.55 (1H, s), 7.92 (1H, s), 8.36 (1H, s), 8.57 (1H, dt), 8.61-8.68(1H, m), 8.94 (1H, s); m/z: ES⁺ MH⁺ 536.53.

Intermediate 58:2-(4-{4-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-N,N-dimethylacetamide

DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 207 mg, 0.5 mmol) andN,N-dimethyl-2-piperazin-1-ylacetamide (86 mg, 0.50 mmol) in2,2,2-trifluoroethanol (2.5 mL). The mixture was heated in a microwaveat 140° C. for 1 h then cooled to r.t. The mixture was purified directlyby ion exchange chromatography, using an SCX column and eluting with 7Mmethanolic ammonia to provide crude product after concentration ofappropriate fractions. Further purification by FCC, eluting with 0-5%CH₃OH in CH₂Cl₂ gave the title compound (234 mg, 83%) as an orange foam;¹H NMR: (CDCl₃) 2.71-2.78 (4H, m), 2.97 (3H, s), 3.09 (3H, s), 3.11-3.18(4H, m), 3.26 (2H, s), 3.99 (3H, s), 6.66 (1H, s), 6.97 (1H, td),7.35-7.42 (1H, m), 7.52 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.56 (1H,d), 8.92 (1H, s), 9.02 (1H, s); m/z: ES⁺ MH⁺ 566.52.

Intermediate 59: (S)-tert-ButylN-[1-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate

A mixture of (S)-tert-butylN-[1-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate(Intermediate 60, 100 mg, 0.15 mmol), iron (51.4 mg, 0.92 mmol) andNH₄Cl (5.74 mg, 0.11 mmol) was heated at reflux in ethanol (3 mL) andwater (1 mL) for 1 h. Purification by ion exchange chromatography, usingan SCX column and eluting with 7M methanolic ammonia provided materialthat was further purified by FCC, eluting with O-5% CH₃OH in CH₂Cl₂ togive the title compound (65 mg, 68%) as a yellow solid; m/z: ES⁺ MH⁺622.58.

Intermediate 60: (S)-tert-ButylN-[1-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylyl-pyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-1-oxopropan-2-yl]-carbamate

DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 207 mg, 0.5 mmol) and (S)-tert-butyl1-oxo-1-(piperazin-1-yl)propan-2-ylcarbamate (129 mg, 0.50 mmol) in2,2,2-trifluoroethanol (2.5 mL). The mixture was heated in a microwaveat 140° C. for 1 h then cooled to r.t. The mixture was purified directlyby ion exchange chromatography, using an SCX column and eluting with 7Mmethanolic ammonia to give crude material. Further purification by FCC,eluting with 0-5% CH₃OH in CH₂Cl₂ gave the title compound (110 mg, 34%)as a solid/gum; m/z: ES⁺ MH⁺ 552.59.

Intermediate 61:N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 62, 295 mg, 0.58 mmol), iron (194 mg, 3.48 mmol) and NH₄Cl(23 mg, 0.43 mmol) were heated at reflux in ethanol (12 mL) and water (4mL) for 1.5h. The mixture was then cooled and concentrated in vacuo. Theresidue was triturated in 10% CH₃OH in CH₂Cl₂ (25 mL) for 15 minutes andthen filtered. The residues were triturated again with 10% CH₃OH inCH₂Cl₂ (25 mL) and filtered. The combined filtrates were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. Purification by FCC,eluting with 2% 7N methanolic ammonia in CH₂Cl₂ gave the title compound(260 mg, 94%) as a yellow gum; ¹H NMR: 1.73-1.86 (1H, m), 2.01-2.12 (1H,m), 2.20 (6H, s), 2.81-2.91 (1H, m), 2.92-3.05 (2H, m), 3.16 (1H, dd),3.2-3.27 (1H, m), 3.67 (3H, s), 4.25 (2H, d), 6.71 (1H, s), 6.93 (1H,s), 7.12 (1H, td), 7.3-7.37 (1H, m), 8.36 (1H, s), 8.38-8.46 (2H, m),8.82 (1H, dt), 8.94 (1H, s); m/z: ES⁺ MH⁺ 479.5.

Intermediate 62:5-Chloro-N-{4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

(3S)—N,N-Dimethylpyrrolidin-3-amine (0.092 mL, 0.72 mmol) was added to asuspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.125 mL, 0.72 mmol) inDMA (3 mL) and the mixture was heated at 140° C. in a microwave for0.5h. The mixture was then diluted with CH₃OH and absorbed onto an SCXcolumn. The column was washed with CH₃OH and then eluted with 1:1 7Mmethanolic ammonia in CH₂Cl₂. Appropriate fractions were concentratedand further purification by FCC, eluting with 2% 7N methanolic ammoniain CH₂Cl₂ gave the title compound (300 mg, 98%) as an orange foam; ¹HNMR: 1.75-1.95 (1H, m), 2.09-2.30 (7H, m), 2.72-2.87 (1H, m), 3.11-3.27(3H, m), 3.42-3.56 (1H, m), 3.90 (3H, s), 6.57 (1H, s), 7.13 (1H, t),7.26-7.41 (1H, m), 8.09 (1H, s), 8.28-8.50 (2H, m), 8.67 (1H, s), 8.84(1H, d), 8.95 (1H, s); m/z: ES⁺ MH⁺ 509.5.

Intermediate 63:N′-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A mixture of5-chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 64, 775 mg, 1.57 mmol), iron (525 mg, 9.40 mmol) and NH₄Cl(62.8 mg, 1.17 mmol) was heated at reflux in ethanol (21 mL) and water(7 mL) for 2 h. The mixture was then cooled and filtered throughdiatomaceous earth (Celite™). The filtrate was concentrated in vacuo andthen dissolved into CH₂Cl₂. This solution was washed with brine, dried(MgSO₄) and concentrated in vacuo. Purification by FCC, eluting with2-6% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (480 mg,66%) as a brown gum; ¹H NMR: 2.26 (3H, s), 2.52 (4H+DMSO, m), 2.89 (4H,t), 3.68 (3H, s), 4.35 (2H, d), 6.73 (1H, s), 6.99 (1H, d), 7.13 (1H,td), 7.28-7.39 (1H, m), 8.38 (1H, d), 8.39-8.46 (2H, m), 8.82 (1H, d),8.95 (1H, s); m/z: ES⁺ MH⁺ 465.5.

Intermediate 64:5-Chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

1-Methylpiperazine (0.267 mL, 2.41 mmol) was added to a suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 500 mg, 1.21 mmol) in 2,2,2-trifluoroethanol (6 mL).The mixture was heated in a microwave at 140° C. for 1 h. The mixturewas then loaded onto a SCX column, and the column was washed with CH₃OH.The column was then eluted with 2M methanolic ammonia and appropriatefractions were combined and concentrated in vacuo. Further purificationby FCC, eluting with 0-10% CH₃OH in CH₂Cl₂ gave the title compound (596mg, 100%), as an orange foam; ¹H NMR: (CDCl₃) 2.37 (3H, s), 2.57-2.68(4H, m), 3.08-3.14 (4H, m), 4.00 (3H, s), 6.64 (1H, s), 6.98 (1H, t),7.34-7.43 (1H, m), 7.53 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.53-8.6(1H, m), 8.93 (1H, s), 9.04 (1H, s); m/z: ES⁺ MH⁺ 495.

Intermediate 65:2-{[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile

A mixture ofN′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 63, 157 mg, 0.34 mmol), zinc (2.209 mg, 0.03 mmol),tris(dibenzylideneacetone)dipalladium(0) (30.9 mg, 0.03 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 32.2mg, 0.07 mmol), and dicyanozinc (23.8 mg, 0.20 mmol) were placed in areaction tube under N₂ and then degassed DMA (0.9 mL) was added. Theresulting suspension was stirred to 95° C. for 1.5h. The mixture wasthen diluted with EtOAc and washed five times with water, then brine.The solution was then dried (MgSO₄) and concentrated in vacuo. Theresidue was triturated with diethyl ether and the resulting solid wascollected by filtration, and washed with diethyl ether. The solid wasthen dissolved in a mixture of CH₂Cl₂ and CH₃OH and the solution wasallowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE(available from Polymer Laboratories) under gravity. The resultingsolution was concentrated in vacuo to give the title compound (87 mg,57%) as a yellow solid; ¹H NMR: (100° C.) 2.28 (3H, s), 2.49-2.58 (4H,m), 2.90-2.98 (4H, m), 3.70 (3H, s), 4.28 (2H, br s), 6.77 (1H, s), 6.99(1H, s), 7.14 (1H, t), 7.37 (1H, t), 8.37 (1H, d), 8.55 (1H, s), 8.78(1H, d), 8.85 (1H, s), 8.92 (1H, s); m/z: ES⁺ MH⁺ 456.4.

Intermediate 66:N′-[4-(1H-Indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A solution of NH₄Cl (0.021 g, 0.38 mmol) in water (3 mL) was added inone portion to a stirred suspension of4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine(Intermediate 67, 0.235 g, 0.51 mmol) and iron (0.171 g, 3.07 mmol) inethanol (9 mL) and the mixture was stirred at 105° C. for 18 h. Themixture was then concentrated in vacuo and the resulting residue wasdissolved in DMF (20 mL). Purification by ion exchange chromatography,using an SCX column, eluting with 0.35M methanolic ammonia in CH₂Cl₂ andconcentration of the appropriate fractions gave the title compound(0.206 g, 94%) as a yellow solid; m/z: ES⁺ MH⁺ 430.51.

Intermediate 67:4-(1H-Indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine

A mixture of 1-methylpiperazine (148 mg, 1.48 mmol),N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 68, 224 mg, 0.59 mmol) and trifluoroethanol (5 mL) wassealed into a microwave tube and heated to 120° C. for 1 h in amicrowave reactor and then cooled to r.t. The mixture was thenconcentrated in vacuo. Trituration of the resulting brown gum withethanol and then diethyl ether gave a solid that was collected byfiltration and dried under vacuum to give the title compound (89 mg,33%) as a pale brown solid; ¹H NMR: 3.02-3.13 (4H, m), 4.00 (3H, s),6.86 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.31 (1H, d), 7.45 (1H, d),8.08 (1H, s), 8.33 (2H, dd), 8.82 (1H, d), 11.81 (1H, s); m/z: ES⁺ MH⁺460.5.

Intermediate 68:N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine

p-Toluenesulfonic acid hydrate (225 mg, 1.18 mmol) was added in oneportion to a mixture of 4-fluoro-2-methoxy-5-nitroaniline (Intermediate23, 200 mg, 1.07 mmol) and 3-(2-chloropyrimidin-4-yl)-1H-indole (247 mg,1.07 mmol) in 2-pentanol (10 mL). The resulting mixture was then stirredat 120° C. for 18 h. The resulting precipitate was collected byfiltration, washed with 2-pentanol (5 mL) and dried in vacuo to give ayellow solid. The solid was triturated with CH₃CN to give a solid whichwas collected by filtration and dried in vacuo to give the titlecompound (224 mg, 55%) as a yellow solid; m/z: ES⁺ MH⁺ 380.21.

Intermediate 69:4-Methoxy-6-(4-methylpiperazin-1-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A solution of[(Z)-3-(dimethylamino)-3-pyrazolo[1,5-a]pyridin-3-yl-prop-2-enylidene]-dimethyl-ammoniumhexafluorophosphate (Intermediate 70, 116 mg, 0.3 mmol) in 2-smethoxyethanol (2 mL) was added dropwise to a stirred solution of1-(5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)guanidine(Intermediate 72, 84 mg, 0.30 mmol) and 1,1,3,3-tetramethylguanidine(0.056 mL, 0.45 mmol) in 2-methoxyethanol (2 mL) at r.t. under N₂. Theresulting solution was sealed into a microwave tube and heated to 120°C. for 0.25 h then cooled to r.t. Further 1,1,3,3-tetramethylguanidine(0.056 mL, 0.45 mmol) was then added and the mixture was stirred at 120°C. for 0.25h, then at 140° C. for 0.25h. The mixture was cooled, dilutedwith EtOAc (10 mL), and washed with water (2×5 mL). The aqueous solutionwas extracted with EtOAc (5 mL) and the organic solution was washed withwater (2×3 mL). The combined organic solutions were dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, eluting with 1.5-5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (69 mg, 53%) as ayellow foam; ¹H NMR: 2.25 (3H, d), 2.51 (4H, m), 2.87 (4H, t), 3.73 (3H,s), 4.37 (2H, s), 6.72 (1H, s), 7.07 (1H, m), 7.22 (1H, d), 7.33 (1H,s), 7.40 (1H, m), 7.98 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H,s), 8.79 (1H, d); m/z: ES⁺ MH⁺ 431.

Intermediate 70:[(Z)-3-(Dimethylamino)-3-pyrazolo[1,5-a]pyridin-3-yl-prop-2-enylidene]-dimethyl-ammoniumhexafluorophosphate

Dimethylamine (24.0 mL, 48.0 mmol, 2M in THF) was added in one portionto a suspension of(Z)—N-(3-chloro-3-(pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminiumhexafluorophosphate (Intermediate 71, 6.07 g, 16 mmol) in CH₃OH (40 mL)at r.t. under N₂. The resulting solution was stirred at r.t. for 0.25 hthen stored in the freezer overnight. Crystals were produced and thesewere collected, washed with CH₃OH at −50° C. and THF, then dried bysuction under a stream of N₂. Two crops of crystals were collected togive the title compound (5.29 g, 85%) as a beige crystalline solid; m/z:ES⁺ M⁺ 244.

Intermediate 71:(Z)—N-(3-Chloro-3-(pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminiumhexafluorophosphate

POCl₃ (0.951 mL, 10.20 mmol) was added to a solution of(E)-3-(dimethylamino)-1-(pyrazolo[1,5-a]pyridin-3-yl)prop-2-en-1-one(2.153 g, 10 mmol) in CH₂Cl₂ (15 mL) at 20° C. (using ice/water cooling)over a period of 3 minutes under N₂. The resulting solution was stirredat r.t. for 0.5 h and was then concentrated in vacuo. The residue wasdissolved into a minimum amount of CH₃OH (100 mL). This solution wasadded over a period of 2 minutes to a solution of sodiumhexafluorophosphate(V) (3.36 g, 20.00 mmol) in CH₃OH (40 mL). After 5minutes the precipitate was collected by filtration, washed well withCH₃OH cooled to −50° C. and dried by suction under a stream of N₂ togive the title compound (3.40 g, 90%) as a yellow powder, which was usedwithout further purification; ¹H NMR: 3.63 (6H, d), 7.36 (2H, m),7.71-7.90 (1H, m), 8.45 (1H, d), 8.81 (1H, d), 9.05 (2H, d); m/z: ES⁺ M⁺234.

Intermediate 72:1-[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]guanidine

A mixture of1-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]guanidine(Intermediate 73, 1.47 g, 4.58 mmol) and 10% Pd on carbon (0.146 g, 0.14mmol) in ethanol (30 mL) was stirred under an atmosphere of H₂ at r.t.for 18 h. The mixture was filtered through diatomaceous earth (Celite™)and the filtrate was concentrated in vacuo.

The residue, together with 10% Pd on carbon (0.146 g, 0.14 mmol) inCH₃OH (60 mL) was stirred under an atmosphere of H₂ at r.t. for 2 h. Themixture was then filtered through diatomaceous earth (Celite™) and thefiltrate was concentrated in vacuo to give the title compound (1.253 g,94%) as a brown foam; ¹H NMR: 2.24 (3H, s), 2.51 (4H, m), 2.86 (4H, m),3.72 (3H, s), 4.47 (2H, s), 6.54 (1H, s), 6.69 (1H, s), 7.30 (3H, s);m/z: ES⁺ MH⁺ 279.

Intermediate 73:1-[2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]guanidine

Methanesulfonic acid (0.508 mL, 7.83 mmol) was added to a slurry of2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline (Intermediate 14,1.39 g, 5.22 mmol) in butan-1-ol (10 mL) and water (0.5 mL) at r.t. Theresulting slurry was heated to 90° C. and at that temperature a solutionof cyanamide (0.439 g, 10.44 mmol) in water (0.22 mL) was added dropwiseover a period of 1 minute. The mixture was heated at 90° C. for 0.5 hthen methanesulfonic acid (0.339 mL, 5.22 mmol) was added dropwise. At10-minute intervals more cyanamide (0.219 g, 5.22 mmol), moremethanesulfonic acid (0.339 mL, 5.22 mmol) and more cyanamide (0.329 g,7.83 mmol) and more methanesulfonic acid (0.339 mL, 5.22 mmol) weresuccessively added. The mixture was allowed to cool and was diluted with2-methyltetrahydrofuran (75 mL) and diethyl ether (75 mL). This solutionwas then basified using 5M NaOH to ˜pH 13. The resulting phases wereseparated and the aqueous solution was extracted with2-methyltetrahydrofuran (3×50 mL). The combined organic solutions werewashed with sat. brine and dried (MgSO₄). The product precipitated ontothe drying agent, so after filtration the MgSO₄ was washed with hotCH₂Cl₂/CH₃OH 5:1 (5×100 mL) and the combined filtrate was concentratedin vacuo. The residue was dissolved in hot 2-s propanol (80 mL),filtered while hot and then concentrated in vacuo. The residue wasdissolved in CH₂Cl₂ (50 mL), filtered and the filtrate was concentratedin vacuo to give the title compound (1.49 g, 89%) as an orange foam. Theproduct could only be deposited amorphously from the 2-propanolfiltrate, but a 38 mg sample of the final product was crystallised fromethanol (˜100 μL) and was collected by filtration, washed with −70° C.ethanol and diethyl ether and dried under vacuum to give the titlecompound (11 mg, 28%) as a yellow powder; ¹H NMR: 2.25 (3H, s),2.44-2.49 (4H, m), 2.99-3.16 (4H, m), 3.91 (3H, s), 6.73 (1H, s), 7.38(3H, s), 7.67 (1H, s); m/z: ES⁺ MH⁺ 309.

Intermediate 74:N′-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A mixture of5-chloro-4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine(Intermediate 75, 350 mg, 0.71 mmol), iron (237 mg, 4.25 mmol) and NH₄Cl(26.5 mg, 0.50 mmol) were heated at reflux in ethanol (24 mL) and water(8 mL) for 2 h. The mixture was then cooled and concentrated in vacuo togive a thick slurry. CH₂Cl₂ (100 mL) and CH₃OH (10 mL) were added andthe mixture was stirred for 0.25 h and then filtered. The filter cakewas washed with further CH₂Cl₂ and CH₃OH, and the combined organics weredried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 1-5% methanolic ammonia in CH₂Cl₂ gave the title compound (288 mg,88%) as a yellow dry film; ¹H NMR: 2.26 (3H, s), 2.47-2.56 (4H, m), 2.88(4H, t), 3.70 (3H, s), 4.29 (2H, d), 6.72 (1H, s), 7.04 (1H, t), 7.14(1H, s), 7.15-7.22 (1H, m), 7.46 (1H, d), 8.18 (1H, s), 8.35 (2H, d),8.48 (1H, d), 11.81 (1H, s); m/z: ES⁺ MH⁺ 464.49.

Intermediate 75:5-Chloro-4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine

1-Methylpiperazine (492 μL, 4.44 mmol) was added to a suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 76, 612 mg, 1.48 mmol). The mixture was heated at 120° C.for 1 h and was then concentrated in vacuo. The residue was dissolved inCH₂Cl₂ (25 mL) and washed with water (2×25 mL) and sat. brine (25 mL),then dried (MgSO₄) and concentrated in vacuo. Purification by FCC,eluting with 1-10% CH₃OH in CH₂Cl₂ gave the title compound as an orangegum. This gum was dissolved in ethanol (25 mL) and a solid precipitated.This solid was collected by filtration and washed with ethanol anddiethyl ether to give the title compound (365 mg, 50%) as ayellow/orange solid; ¹H NMR: 2.26 (3H, s), 2.47-2.55 (4H, m), 3.07-3.13(4H, m), 3.93 (3H, s), 6.85 (1H, s), 6.99 (1H, t), 7.16-7.22 (1H, m),7.48 (1H, d), 8.26 (1H, d), 8.36 (1H, s), 8.42 (1H, d), 8.51 (1H, s),8.54 (1H, s), 11.88 (1H, s); m/z: ES⁺ MH⁺ 494.46.

Intermediate 76:5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)-pyrimidin-2-amine

A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 11,391 mg, 1.48 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23,289 mg, 1.55 mmol) and p-toluenesulfonic acid monohydrate (310 mg, 1.63mmol) in 2-pentanol (25 mL) was heated at 125° C. for 18 h. The mixturewas cooled and used in the next step without further purification; m/z:ES⁺ MH⁺ 414.12.

Intermediate 77:4-Methoxy-N′-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A mixture ofN-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 78, 408 mg, 0.84 mmol), iron (280 mg, 5.02 mmol) and NH₄Cl(31.3 mg, 0.59 mmol) in ethanol (24 mL) and water (8.00 mL) was heatedat reflux for 3 h. The mixture was cooled and concentrated in vacuo togive a thick slurry. CH₂Cl₂ (100 mL) and CH₃OH (10 mL) were added andthe mixture was stirred for 0.25 h and then filtered. The filter cakewas washed with further CH₂Cl₂ and CH₃OH and the combined organics weredried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 1-7% methanolic ammonia in CH₂Cl₂ gave the title compound (163 mg,43%) as a yellow gum which crystallised on standing; ¹H NMR: (CDCl₃)2.36 (6H, s), 2.53 (3H, dd), 2.94 (4H, t), 3.69-3.79 (2H, m), 3.83 (3H,s), 3.86 (3H, s), 6.69 (1H, s), 7.24-7.27 (1H, m), 7.29 (1H, dd), 7.33(1H, dd), 7.36-7.40 (1H, m), 7.49 (1H, s), 7.58 (1H, s), 8.23 (1H, d),8.26 (1H, s), 8.56 (1H, d); m/z: ES⁺ MH⁺ 458.37.

Intermediate 78:N-[2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine

1-Methylpiperazine (0.453 mL, 4.08 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 79, 554 mg, 1.36 mmol) in 2,2,2-trifluoroethanol (10 mL).The mixture was heated in a microwave at 120° C. for 1 h. The mixturewas then concentrated in vacuo and the residue was dissolved in CH₂Cl₂(50 mL). This solution was washed water (2×50 mL) and sat. brine (50mL), then dried (MgSO₄) and concentrated in vacuo. Purification by FCC,eluting with 1-10% CH₃OH in CH₂Cl₂ gave an orange gum. This gum wasdissolved in ethanol (25 mL) and a solid precipitated. This solid wascollected by filtration and washed with ethanol to give the titlecompound (413 mg, 62%) as a yellow/orange solid; ¹H NMR: 2.25 (3H, s),2.39 (3H, s), 2.45-2.54 (4H, m), 3.03-3.10 (4H, m), 3.91 (3H, s), 3.98(3H, s), 6.86 (1H, s), 7.06 (1H, dd), 7.22-7.28 (1H, m), 7.51 (1H, d),8.02 (1H, s), 8.07 (1H, s), 8.26-8.30 (1H, m), 8.38 (1H, d), 8.69 (1H,s); m/z: ES⁺ MH⁺ 488.29.

Intermediate 79:N-(4-Fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine

A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-indole(Intermediate 80, 350 mg, 1.36 mmol), 4-fluoro-2-methoxy-5-nitroaniline(Intermediate 23, 265 mg, 1.43 mmol) and p-toluenesulfonic acid (284 mg,1.49 mmol) in 2-pentanol (25 mL) was heated at 125° C. for 24 h. Themixture was then cooled and concentrated in vacuo. The resulting gum wasused without further purification; m/z: ES⁺ MH⁺ 240.13.

Intermediate 80: 3-(2-Chloro-5-methylpyrimidin-4-yl)-1H-indole

NaH (0.862 g, 21.54 mmol, 30% dispersion in mineral oil) was added to3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (Intermediate 17, 5.0 g,20.5 mmol) in THF (200 mL) at 0° C. under N₂. The resulting solution wasstirred at 0° C. for 0.25h. CH₃I (1.347 mL, 21.54 mmol) was then added,the mixture was allowed to warm to r.t. and was stirred for 2 h. Themixture was cooled again in an ice bath and further NaH (0.862 g, 21.54mmol, 30% dispersion in mineral oil) was added. The resulting suspensionwas stirred at 0° C. for 10 minutes. CH₃I (1.347 mL, 21.54 mmol) wasthen added and the mixture was stirred for a further 1 h. The mixturewas then diluted with water (100 mL) and extracted with EtOAc (100 mL).The organic solution was washed with water (75 mL) and some solid formedat the solvent interface. The solid was collected by filtration and waswashed with water and EtOAc and then dried, giving the title compound asa white solid. The phases were separated and the organic solution wasfurther washed with water and some more solid formed so this was alsocollected by filtration, washed with water and EtOAc and dried, to givemore of the title compound as a white solid. (total so far: 3.82 g,72%). The organic solution was then washed with sat. brine, dried(MgSO₄) and concentrated in vacuo. The residue was triturated withdiethyl ether to give a solid which was collected by filtration anddried in vacuo to give the title compound (0.883 g, 17%) as a beigesolid; (overall: 4.71 g, 89%); ¹H NMR: 2.48 (3H, s), 3.94 (3H, s),7.24-7.36 (2H, m), 7.58 (1H, d), 8.25 (1H, s), 8.48 (1H, s), 8.57 (1H,d); m/z: ES⁺ MH⁺ 258.12.

Intermediate 81:N¹-(2-Dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

A mixture ofN′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N-[5-methyl-4-(1-methyl-indol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine(Intermediate 82, 202 mg, 0.41 mmol), iron (138 mg, 2.48 mmol) and NH₄Cl(15.45 mg, 0.29 mmol) in ethanol (16 mL) and water (5.33 mL) was heatedat reflux for 3 h. The mixture was then cooled and concentrated in vacuoto give a thick slurry. CH₂Cl₂ (100 mL) and CH₃OH (10 mL) was then addedand the mixture was stirred for 0.25 h and then filtered. The filtercake was washed further with CH₂Cl₂ and CH₃OH and the combined organicswere dried (MgSO₄) and concentrated in vacuo. Purification by FCC,eluting with 1-8% methanolic ammonia in CH₂Cl₂ gave the title compound(147 mg, 78%) as a yellow dry film; m/z: ES⁺ MH⁺ 460.36.

Intermediate 82:N′-(2-Dimethylaminoethyl)-2-methoxy-N′-methyl-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

N¹,N¹,N²-Trimethylethane-1,2-diamine (221 mg, 2.16 mmol) was added to asuspension ofN-(4-Fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 79, 400 mg, 0.98 mmol) in DMA (4 mL). The mixture washeated in a microwave at 140° C. for 0.5h. The mixture was thenconcentrated in vacuo and the residue was dissolved in EtOAc (100 mL).This solution was washed with water (2×100 mL) and sat. brine (100 mL),dried (MgSO₄) and concentrated in vacuo. Purification by FCC, elutingwith 1-8% methanolic ammonia in CH₂Cl₂ gave the title compound (202 mg,42%) as an orange dry film; m/z: ES⁺ MH⁺ 444.55.

Intermediate 83:4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 84, 325 mg, 0.65 mmol), iron (217 mg, 3.89 mmol) and NH₄Cl(24.26 mg, 0.45 mmol) in ethanol (16 mL) and water (5.33 mL) was heatedat reflux for 3 h. The mixture was then cooled and concentrated in vacuoto give a thick slurry. CH₂Cl₂ (100 mL) and CH₃OH (10 mL) were thenadded and the mixture was stirred for 0.25 h and then filtered. Thefilter cake was washed with further CH₂Cl₂ and CH₃OH and the combinedorganics were dried (MgSO₄) and concentrated in vacuo. Purification byFCC, eluting with 1-8% methanolic ammonia in CH₂Cl₂ gave the titlecompound (257 mg, 84%) as a yellow dry film; ¹H NMR: 1.76 (1H, td), 2.03(1H, dt), 2.18 (6H, s), 2.37 (3H, s), 2.79-2.87 (1H, m), 2.88-2.97 (2H,m), 3.08-3.14 (1H, m), 3.18 (1H, dd), 3.73 (3H, s), 3.90 (3H, s), 4.19(2H, s), 6.70 (1H, s), 7.13 (1H, t), 7.25 (1H, t), 7.44 (1H, s), 7.51(1H, d), 7.65 (1H, s), 8.04 (1H, s), 8.19 (1H, s), 8.46 (1H, d); m/z:ES⁺ MH⁺ 472.35.

Intermediate 84:N-{4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine

(3R)—N,N-dimethylpyrrolidin-3-amine (255 mg, 2.24 mmol) was added to asuspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 79, 414 mg, 1.02 mmol) in DMA (4 mL) and the mixture washeated in a microwave at 140° C. for 0.5h. The mixture was thenconcentrated in vacuo and the residue was dissolved in EtOAc (50 mL).Purification by ion exchange chromatography, using an SCX column andeluting with 0.35M methanolic ammonia provided semi-purified materialafter concentration of appropriate fractions in vacuo. Purification byFCC, eluting with 1-8% CH₃OH in CH₂Cl₂ gave the title compound (330 mg,65%) as an orange dry film; ¹H NMR: 1.75-1.86 (1H, m), 2.13-2.19 (1H,m), 2.21 (6H, s), 2.37 (3H, s), 2.75 (1H, s), 3.10-3.20 (2H, m),3.21-3.27 (1H, m), 3.46 (1H, td), 3.90 (3H, s), 3.94 (3H, s), 6.56 (1H,s), 7.03 (1H, t), 7.21-7.26 (1H, m), 7.49 (1H, d), 7.94 (1H, s), 8.05(1H, s), 8.23 (1H, s), 8.37 (1H, d), 8.39 (1H, s); m/z: ES⁺ MH⁺ 502.33.

Intermediate 85:N-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 86, 747 mg, 1.43 mmol), iron (479 mg, 8.59 mmol) and NH₄Cl(53.6 mg, 1.00 mmol) in ethanol (48 mL) and water (16 mL) was heated atreflux for 3 h. The mixture was then cooled and concentrated in vacuo togive a thick slurry. CH₂Cl₂ (100 mL) and CH₃OH (10 mL) were then addedand the mixture was stirred for 0.25 h and then filtered. The filtercake was washed with further CH₂Cl₂ and MeOH and the combined organicswere dried (MgSO₄) and concentrated in vacuo. Purification by FCC (splitinto two batches), eluting with 1-9% methanolic ammonia in CH₂Cl₂ gavethe title compound (230 mg, 33%) as a yellow gum which crystallised onstanding, and (2^(nd) batch) more of the title compound (329 mg, 47%) asa yellow gum; ¹H NMR: (CDCl₃) 1.87 (1H, ddt), 2.13 (1H, dtd), 2.29 (6H,s), 2.86 (1H, dq), 2.98-3.09 (2H, m), 3.20 (2H, dd), 3.66 (2H, s), 3.84(3H, s), 3.88 (3H, s), 6.70 (1H, s), 7.25-7.35 (2H, m), 7.38 (1H, dd),7.61 (1H, s), 8.10 (1H, s), 8.19 (1H, d), 8.32 (1H, s), 8.66 (1H, dd);m/z: ES⁺ MH⁺ 492.27.

Intermediate 86:5-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine

(3R)—N,N-Dimethylpyrrolidin-3-amine (126 mg, 1.11 mmol) was added to asuspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 87, 215 mg, 0.50 mmol) in DMA (5 mL) and the mixture washeated in a microwave at 140° C. for 0.5h. The mixture was thenconcentrated in vacuo and combined with material from the reaction belowfor work up. (3R)—N,N-dimethylpyrrolidin-3-amine (276 mg, 2.42 mmol) wasadded to a suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 87, 470 mg, 1.10 mmol) in DMA (10 mL) and the mixture washeated in a microwave at 140° C. for 0.5h. The mixture was concentratedin vacuo and combined with the material from the first proceduredescribed above, for work-up. The combined residues were dissolved inCH₂Cl₂ (100 mL), and the resulting solution was washed with water (2×100mL) and sat. brine (100 mL), and then dried (MgSO₄) and concentrated invacuo, Purification by FCC, eluting with 1-10% CH₃OH in CH₂Cl₂ gave thetitle compound (747 mg, 89%) as an orange gum; m/z: ES⁺ M⁺ 522.30.

Intermediate 87:5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine

A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1-methylindole (Intermediate88, 1281 mg, 4.60 mmol), p-toluene sulphonic acid monohydrate (964 mg,5.07 mmol) and 4-fluoro-2-s methoxy-5-nitroaniline (Intermediate 23, 900mg, 4.84 mmol) in 2-pentanol (50 mL) was heated at 125° C. for 18 h. Aprecipitate formed from the solution upon cooling. The precipitate wascollected by filtration, washed with CH₃OH (10 mL) and diethyl ether (20mL) and dried on the filter to give the title compound (1.42 g, 72%) asa tan solid, which was used without further purification; ¹H NMR: 3.91(3H, s), 3.96 (3H, s), 7.05 (1H, t), 7.23-7.3 (1H, m), 7.39 (1H, d),7.53 (1H, d), 8.33 (1H, d), 8.47 (1H, s), 8.58 (1H, s), 8.65 (1H, d),8.76 (1H, s); m/z: ES⁺ MH⁺ 428.10.

Intermediate 88: 3-(2,5-Dichloropyrimidin-4-yl)-1-methylindole

NaH (0.795 g, 19.88 mmol) was added to3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 11, 5.0 g, 18.9mmol) in THF (200 mL) at 0° C. under N₂ and the mixture was stirred at0° C. for 0.25h. CH₃I (1.243 mL, 19.88 mmol) was then added and themixture was allowed to warm to r.t. and was stirred for 1 h. The mixturewas cooled again in an ice bath and further NaH (0.795 g, 19.88 mmol)was added. The suspension was stirred at 0° C. for 10 minutes then CH₃I(1.243 mL, 19.88 mmol) was added and the mixture was stirred for 1 h.The mixture was then diluted with water (100 mL) which resulted in theformation of some solid. The solid was collected by filtration and waswashed with water and EtOAc and then dried, to give the title compound(3.67 g, 70%) as a beige solid. The organic solution was further washedwith water and sat. brine and then dried (MgSO₄) and concentrated invacuo. Trituration of the residue with diethyl ether gave a solid whichwas collected by filtration and dried in vacuo to give the titlecompound (477 mg, 9%) as a brown solid: This material was only 71% pureso it was kept separate from the earlier batch; ¹H NMR: 3.97 (3H, s),7.34 (2H, dtd), 7.59-7.65 (1H, m), 8.56 (1H, dd), 8.73 (1H, s), 8.79(1H, s); m/z: ES⁺ MH⁺ 278.06.

Intermediate 89:2-({5-Amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile

A mixture ofN-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethyl-aminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine(Intermediate 85, 324 mg, 0.66 mmol), zinc powder (4.3 mg, 0.07 mmol),tris(dibenzylideneacetone)-dipalladium(0) (60.3 mg, 0.07 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 62.8mg, 0.13 mmol), and dicyanozinc (46.4 mg, 0.40 mmol) was placed in areaction tube under N₂ and then degassed DMA (1.75 mL) was added. Theresulting suspension was heated to 95° C. and stirred for 2 h. Themixture was then diluted with EtOAc and washed 5 times with water, andthen with brine. The solution was the dried (MgSO₄) and concentrated invacuo. The residue was dissolved in CH₃OH and was allowed to passthrough a stratospheres SPE cartridge PL-Thiol MP SPE (available fromPolymer Laboratories) under gravity. The resulting solution wasconcentrated in vacuo and the resulting residue was triturated withdiethyl ether. The resulting solid was collected by filtration andwashed with diethyl ether to give the title compound (184 mg, 58%) as ayellow solid; ¹H NMR: (100° C.) 1.8-1.88 (1H, m), 2.03-2.11 (1H, m),2.24 (6H, s), 2.92-2.99 (1H, m), 3.01-3.05 (1H, m), 3.06-3.11 (1H, m),3.20 (2H, ddd), 3.69 (3H, s), 3.90 (3H, s), 4.17 (2H, br s), 6.73 (1H,s), 7.04 (1H, s), 7.10 (1H, t), 7.26 (1H, t), 7.50 (1H, d), 8.31 (1H,d), 8.42 (1H, s), 8.60 (1H, s), 8.62 (1H, s); m/z: ES⁺ MH⁺ 483.31.

Intermediate 90:2-{[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile

A mixture ofN′-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 91, 344 mg, 0.72 mmol), zinc powder (4.71 mg, 0.07 mmol),tris(dibenzylideneacetone)dipalladium(0) (65.9 mg, 0.07 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 68.6mg, 0.14 mmol), and dicyanozinc (50.7 mg, 0.43 mmol) were placed in areaction tube under N₂ and then degassed DMA (1.91 mL) was added. Theresulting suspension was shirred at 95° C. for 2 h. The mixture was thendiluted with EtOAc and washed 5 times with water, and then with brine.The solution was then dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved in CH₃OH and allowed to pass through astratospheres SPE cartridge PL-Thiol MP SPE (available from PolymerLaboratories) under gravity. The resulting solution was concentrated invacuo and the resulting residue was triturated with diethyl ether. Theresulting solid was collected by filtration and washed with diethylether to give the title compound (208 mg, 62%) as a yellow solid; ¹HNMR: 2.28 (3H, s), 2.51-2.58 (4H, m), 2.89-2.95 (4H, m), 3.69 (3H, s),3.91 (3H, s), 4.23 (2H, br s), 6.75 (1H, s), 7.08 (1H, s), 7.09-7.12(1H, m), 7.26 (1H, ddd), 7.50 (1H, d), 8.31 (1H, d), 8.43 (1H, s), 8.61(1H, s), 8.64 (1H, s); m/z: ES⁺ MH⁺ 469.33.

Intermediate 91:N′-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A mixture of5-chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 92, 750 mg, 1.48 mmol), iron (495 mg, 8.86 mmol) and NH₄Cl(55.3 mg, 1.03 mmol) in ethanol (12 mL) and water (4 mL) was heated atreflux for 4 h. Purification by ion exchange chromatography, using anSCX column and eluting with 7M methanolic ammonia provided part-purifiedmaterial that was concentrated in vacuo onto silica. Purification byFCC, eluting with 0-4% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (367 mg, 52%) as a yellow solid. Impure fractions containingdesired product were concentrated in vacuo and the resulting residue wastriturated with CH₂Cl₂/diethyl ether to give more of the title compound(230 mg, 33%) as a yellow solid. Total: 597 mg, 85%; ¹H NMR: (CDCl₃)2.37 (3H, s), 2.56 (4H, br s), 2.95 (4H, br t), 3.75 (2H, br s), 3.84(3H, s), 3.90 (3H, s), 6.70 (1H, s), 7.27-7.36 (2H, m), 7.38-7.42 (1H,m), 7.63 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.63-8.69(1H, m); m/z: ES⁺ MH⁺ 478.55.

Intermediate 92:5-Chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

1-Methylpiperazine (0.50 mL, 4.51 mmol) was added to a suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 87, 750 mg, 1.75 mmol) in 2,2,2-trifluoroethanol (15 mL)and the mixture was heated in a microwave at 120° C. for 1 h and then140° C. for 0.5h. The mixture was then concentrated in vacuo and theresidue was dissolved in EtOAc (100 mL). This organic solution waswashed with sat. NaHCO₃ (100 mL), water (2×100 mL) and then brine (100mL). The solution was then dried (MgSO₄) and concentrated in vacuo ontosilica. Purification by FCC, eluting with 0-4% CH₃OH in CH₂Cl₂ gave thetitle compound (772 mg, 87%) as a orange solid; ¹H NMR: (CDCl₃) 2.37(3H, s), 2.59-2.65 (4H, m), 3.07-3.14 (4H, m), 3.90 (3H, s), 3.99 (3H,s), 6.63 (1H, s), 7.25-7.3 (1H, m) partially obscured by chloroformpeak, 7.31-7.36 (1H, m), 7.39 (1H, d), 7.56 (1H, s), 8.22 (1H, s), 8.39(1H, s), 8.47 (1H, d), 9.18 (1H, s); m/z: ES⁺ MH⁺ 508.19.

Intermediate 93:N-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethyl-aminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitro-phenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 94, 350 mg, 0.69 mmol), iron (231 mg, 4.13 mmol) and NH₄Cl(27.6 mg, 0.52 mmol) in ethanol (15 mL) and water (5 mL) was heated atreflux for 1.5h. The mixture was then cooled and concentrated in vacuo.The residue was triturated with 10% CH₃OH in CH₂Cl₂ (15 mL) for 0.25 hand then filtered. The residues were triturated again with 10% CH₃OH inCH₂Cl₂ (15 mL) and then filtered. The combined filtrates were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. Purification byFCC, eluting with 3% CH₃OH in CH₂Cl₂ and then 2-5% 7N methanolic ammoniain CH₂Cl₂ gave the title compound (261 mg, 79%) as a yellow foam; ¹HNMR: 1.73-1.86 (1H, m), 1.99-2.12 (1H, m), 2.20 (6H, s), 2.81-2.91 (1H,m), 2.97 (2H, ddd), 3.12-3.26 (2H, m), 3.69 (3H, s), 4.20 (2H, d), 6.71(1H, s), 7.03 (1H, t), 7.07 (1H, s), 7.14-7.22 (1H, m), 7.46 (1H, d),8.18 (1H, s), 8.3-8.39 (2H, m), 8.48 (1H, s), 11.81 (1H, s); m/z: ES⁺MH⁺ 478.5.

Intermediate 94:5-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine

(R)-(+)-3-(Dimethylamino)pyrrolidine (0.111 mL, 0.87 mmol) was added toa suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) inDMA (3 mL) and the mixture was heated at 140° C. in a microwave for0.5h. The mixture was then diluted with CH₃OH and absorbed onto an SCXcolumn. The column was washed with CH₃OH and eluted with 1:1 methanolicammonia in CH₂Cl₂. Appropriate fractions were concentrated and furtherpurification by FCC, eluting with 1.5% 7N methanolic ammonia in CH₂Cl₂gave the title compound (353 mg, 96%) as an orange foam; ¹H NMR:1.78-1.91 (1H, m), 2.16-2.27 (7H, m), 2.70-2.85 (1H, m), 3.12-3.29 (3H,m), 3.41-3.55 (1H, m), 3.89 (3H, s), 6.57 (1H, s), 6.95 (1H, t), 7.17(1H, t), 7.46 (1H, d), 8.09 (1H, s), 8.24 (1H, br s), 8.37 (1H, s), 8.50(1H, d), 8.54 (1H, s), 11.88 (1H, s); m/z: ES⁺ MH⁺ 508.5.

Intermediate 95:N⁴-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N¹-(2-dimethylamino-ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

A mixture ofN-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine(Intermediate 96, 350 mg, 0.71 mmol), iron (236 mg, 4.23 mmol) and NH₄Cl(28.3 mg, 0.53 mmol) in ethanol (15 mL) and water (5 mL) were heated atreflux for 1.5h. The mixture was then cooled and concentrated in vacuo.The residue was triturated in 10% CH₃OH in CH₂Cl₂ (15 mL) for 0.25 h andthen filtered. The residues were triturated again with 10% CH₃OH inCH₂Cl₂ (15 mL) and then filtered. The combined filtrates were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. Purification byFCC, eluting with 5% CH₃OH in CH₂Cl₂ and then 2-5% 7N methanolic ammoniain CH₂Cl₂ gave the title compound (159 mg, 48%) as a yellow foam; ¹HNMR: 2.18 (6H, s), 2.38 (2H, t), 2.66 (3H, s), 2.91 (2H, t), 3.68 (3H,s), 4.54 (2H, s), 6.77 (1H, s), 6.99-7.10 (2H, m), 7.12-7.22 (1H, m),7.46 (1H, d), 8.25 (1H, s), 8.30-8.40 (2H, m), 8.49 (1H, d), 11.85 (1H,s); m/z: ES⁺ MH⁺ 466.6.

Intermediate 96:N-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N′-(2-dimethyl-aminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamineN,N,N′-Trimethylethylenediamine (0.113 mL, 0.87 mmol) was added to asuspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) inDMA (3 mL) and the mixture was heated at 140° C. in a microwave for0.5h. The mixture was then diluted with CH₃OH and absorbed onto an SCXcolumn. The column was washed with CH₃OH and eluted with 1:1 methanolicammonia in CH₂Cl₂. Appropriate fractions were concentrated andpurification by FCC, eluting with 2% 7N methanolic ammonia in CH₂Cl₂gave the title compound (354 mg, 98%) as an orange foam; ¹H NMR: 2.16(6H, s), 2.52 (2H+DMSO, m), 2.87 (3H, s), 3.30 (2H, t), 3.89 (3H, s),6.84 (1H, s), 6.97 (1H, t), 7.13-7.23 (1H, m), 7.46 (1H, d), 8.16 (1H,s), 8.23 (1H, br d), 8.40 (1H, s), 8.51 (1H, d), 8.55 (1H, s), 11.89(1H, s); m/z: ES⁺ MH⁺ 469.5. Intermediate 97:N⁴-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

A mixture ofN-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N′-(2-dimethylamino-ethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine(Intermediate 98, 553 mg, 1.08 mmol), iron (363 mg, 6.51 mmol) and NH₄Cl(43.5 mg, 0.81 mmol) in ethanol (23 mL) and water (7.67 mL) were heatedat reflux for 1.5h. The mixture was then cooled and concentrated invacuo. The resulting residue was dissolved in CH₂Cl₂ (100 mL) and CH₃OH(10 mL) and this mixture was stirred for 0.25 h and then filtered. Thefilter cake was washed with further CH₂Cl₂ and CH₃OH and the combinedorganics were dried (MgSO₄) and concentrated in vacuo. Purification byFCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ provided a solid.This solid was dissolved in diethyl ether and a small amount of brownprecipitate was removed by filtration. The filtrate was concentrated invacuo to give the title compound (409 mg, 79%) as a brown glass; ¹H NMR:(CDCl₃) 2.26 (6H, s), 2.38-2.43 (2H, m), 2.68 (3H, s), 2.94-2.98 (2H,m), 3.84 (3H, s), 3.91 (3H, s), 6.71 (1H, s), 7.26-7.36 (2H, m), 7.40(1H, d), 7.63 (1H, s), 8.09 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.67(1H, d); m/z: ES⁺ MH⁺ 480.32.

Intermediate 98:N-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine

N¹,N¹,N²-trimethylethane-1,2-diamine (0.189 mL, 1.49 mmol) was added toa suspension5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 87, 700 mg, 1.24 mmol) and DIPEA (0.431 mL, 2.48 mmol) inDMA (5 mL). The mixture was then heated in a microwave at 140° C. for0.5h. The mixture was diluted with CH₃OH and absorbed onto an SCXcolumn. The column was washed with CH₃OH and eluted with ˜1M methanolicammonia. Appropriate fractions were concentrated and furtherpurification by FCC, eluting with 0-5% methanolic ammonia in CH₂Cl₂ gavethe title compound (561 mg, 89%) as an orange oil; ¹H NMR: (CDCl₃) 2.26(6H, s), 2.53-2.58 (2H, m), 2.88 (3H, s), 3.24-3.28 (2H, m), 3.91 (3H,s), 3.98 (3H, s), 6.68 (1H, s), 7.26-7.3 (1H, m), 7.31-7.4 (2H, m), 7.50(1H, s), 8.23 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.07 (1H, s); m/z:ES⁺ MH⁺ 510.27.

Intermediate 99:2-{[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile

N′-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine(Intermediate 74, 268 mg, 0.58 mmol), zinc powder (3.78 mg, 0.06 mmol),tris(dibenzylideneacetone)dipalladium(0) (52.9 mg, 0.06 mmol),dicyclo-hexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’,55.1 mg, 0.12 mmol), and dicyanozinc (40.7 mg, 0.35 mmol) were placed ina flask under N₂ and then degassed DMA (3 mL) was added. The resultingsuspension was stirred for 3 h at 95° C. The mixture was then dilutedwith EtOAc and washed 5 times with water and then brine. The solutionwas then dried (MgSO₄) and concentrated in vacuo. The resulting residuewas triturated with diethyl ether and the resulting solid was collectedby filtration and washed with diethyl ether to give crude product. Thiscrude material was dissolved into CH₂Cl₂/CH₃OH and concentrated in vacuoonto silica. Purification by FCC, eluting with 1.5-8% 7N methanolicammonia in CH₂Cl₂ provided a solid which was washed with CH₃OH (0.2 mL)to give the title compound (48 mg, 18%) as a beige crystalline solid; ¹HNMR: 2.26 (3H, s), 2.53 (4H, m), 2.91 (4H, s), 3.65 (3H, s), 4.38 (2H,d), 6.74 (1H, s), 6.85 (1H, s), 6.99 (1H, s), 7.19 (1H, s), 7.48 (1H,d), 8.01 (1H, s), 8.52 (1H, s), 8.65 (1H, s), 9.21 (1H, s), 11.97 (1H,s); m/z: ES⁺ MH⁺ 455.

Intermediate 100:N¹-(2-Dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

A mixture ofN′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine(Intermediate 101, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) andNH₄Cl (17.32 mg, 0.32 mmol) in ethanol (12 mL) and water (4 mL) washeated at reflux for 2 h. The crude mixture was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M methanolic ammonia and appropriate fractions werecombined and concentrated in vacuo onto silica. Purification by FCC,eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (175 mg, 85%) as a beige foam; ¹H NMR: 2.17 (6H, s), 2.36 (2H,t), 2.63 (3H, s), 2.88 (2H, t), 3.74 (3H, s), 3.88 (3H, s), 4.58 (2H, brs), 6.76 (1H, s), 7.12-7.19 (2H, m), 7.21-7.27 (1H, m), 7.48 (1H, s),7.51 (1H, d), 7.78 (1H, s), 8.27 (1H, d), 8.30 (1H, s), 8.42 (1H, d);m/z: ES⁺ MH⁺ 446.32.

Intermediate 101:N′-(2-Dimethylaminoethyl)-2-methoxy-N′-methyl-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

N¹,N¹,N²-trimethylethane-1,2-diamine (80 mg, 0.79 mmol) was added to asuspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129, (which may be prepared by the method described forIntermediate 87); 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol) in2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at140° C. for 1 h. The cooled reaction mixture was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M methanolic ammonia and appropriatefractions were combined and concentrated in vacuo onto silica.Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH₂Cl₂gave the title compound (230 mg, 62%) as an orange solid; ¹H NMR: 2.16(6H, s), 2.45-2.49 (2H, t, obscured by DMSO peak), 2.86 (3H, s), 3.26(2H, t), 3.87 (3H, s), 3.95 (3H, s), 6.85 (1H, s), 7.11 (1H, t), 7.21(1H, d), 7.25 (1H, t), 7.52 (1H, d), 8.10 (1H, s), 8.31 (1H, d), 8.33(1H, s), 8.36 (1H, d), 8.62 (1H, s); m/z: ES⁺ MH⁺ 476.40.

Intermediate 102:2-{[5-Amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile

N⁴-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine(Intermediate 97, 250 mg, 0.52 mmol), zinc (3.41 mg, 0.05 mmol),tris(dibenzylideneacetone)dipalladium(0) (47.7 mg, 0.05 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 49.7mg, 0.10 mmol), and dicyanozinc (36.7 mg, 0.31 mmol) were placed in areaction tube under N₂ and then degassed DMA (1.38 mL) was added. Theresulting suspension was shined for 3.5 h at 95° C. The mixture was thendiluted with EtOAc and washed 5 times with water, and then brine. Thesolution was then dried (MgSO₄) and concentrated in vacuo. The residuewas dissolved in CH₃OH/CH₂Cl₂ and the solution was allowed to passthrough a stratospheres SPE cartridge PL-Thiol MP SPE (available fromPolymer Laboratories)under gravity. The resulting solution wasconcentrated in vacuo and the residue was triturated with diethyl ether.The resulting solid was collected by filtration and washed with diethylether to give the title compound (80 mg) as yellow solid. The aqueouswork-up solutions were purified by ion exchange chromatography, using anSCX column. The desired product was eluted from the column using 7Mmethanolic ammonia and pure fractions were concentrated in vacuo to givea brown oil (126 mg). Purification by FCC, eluting with 0-5% methanolicammonia in CH₂Cl₂ gave the title compound (94 mg) as a yellow solid.Both batches of product were combined to give (174 mg, 71%) as a yellowsolid; m/z: ES⁺ MH⁺ 471.33.

Intermediate 103:4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture of(N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 104, 360 mg, 0.74 mmol), iron (247 mg, 4.43 mmol) andNH₄Cl (27.6 mg, 0.52 mmol) in ethanol (12 mL) and water (4 mL) washeated at reflux for 2 h. The crude mixture was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M methanolic ammonia and appropriate fractions werecombined and concentrated in vacuo onto silica. Purification by FCC,eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (280 mg, 83%) as a beige foam; ¹H NMR: 1.69-1.83 (1H, m),1.97-2.10 (1H, m), 2.18 (6H, s), 2.78-2.87 (1H, m), 2.88-2.98 (2H, m),3.11 (1H, dd), 3.15-3.22 (1H, m), 3.74 (3H, s), 3.87 (3H, s), 4.29 (2H,br s), 6.70 (1H, s), 7.1-7.19 (2H, m), 7.21-7.28 (1H, m), 7.46 (1H, s),7.51 (1H, d), 7.78 (1H, s), 8.25 (1H, d), 8.29 (1H, s), 8.43 (1H, d);m/z: ES⁺ MH⁺ 458.35.

Intermediate 104:N-[4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

(3R)—N,N-Dimethylpyrrolidin-3-amine (107 mg, 0.94 mmol) was added to asuspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129; (which may be prepared by the method described forIntermediate 87), 0.372 mL, 2.13 mmol) in 2,2,2-trifluoroethanol (5 mL)and the mixture was heated in a microwave at 140° C. for 1 h. The cooledmixture was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7Mmethanolic ammonia and appropriate fractions were combined andconcentrated in vacuo onto silica. Purification by FCC, eluting with0-4% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (364 mg,87%) as an orange solid; ¹H NMR: 1.74-1.87 (1H, m), 2.11-2.22 (1H, m),2.21 (6H, s), 2.70-2.81 (1H, m), 3.10-3.21 (2H, m), 3.21-3.28 (1H, m),3.47 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 6.56 (1H, s), 7.10 (1H, t),7.18 (1H, d), 7.21-7.27 (1H, m), 7.51 (1H, d), 8.07 (1H, s), 8.29 (1H,d), 8.32 (1H, s), 8.36 (1H, d), 8.54 (1H, s); m/z: ES⁺ MH⁺ 488.31.

Intermediate 105:N⁴-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5-methoxy-N¹-methyl-N¹-(2-morpholin-4-ylethyl)benzene-1,2,4-triamine

A solution of NH₄Cl (28.1 mg, 0.53 mmol) in water (13.00 mL) was addedin one portion to a stirred mixture ofN-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-(2-morpholin-4-ylethyl)-5-nitrobenzene-1,4-diamine(Intermediate 106, 426 mg, 0.75 mmol) and iron (251 mg, 4.50 mmol) inethanol (39 mL). The resulting mixture was stirred at reflux for 2 h.Further iron (251 mg, 4.50 mmol) and NH₄Cl (28.1 mg, 0.53 mmol) wasadded and the mixture was stirred at reflux for a further 0.5h. Themixture was concentrated in vacuo and the residue was mixed with DMF (5mL) and then purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7Mmethanolic ammonia in CH₂Cl₂ and appropriate fractions were combined andconcentrated in vacuo. Purification by FCC, eluting with 1.5-7% 2Mmethanolic ammonia in CH₂Cl₂ gave the title compound (304 mg, 80%) as ayellow foam; ¹H NMR: 2.43 (4H, m), 2.45 (2H, t), 2.68 (3H, s), 2.93 (2H,t), 3.51-3.61 (4H, m), 3.66 (3H, s), 4.73 (2H, s), 6.77 (1H, s), 6.90(1H, s), 7.12 (1H, m), 7.34 (1H, m), 8.37 (1H, s), 8.43 (1H, d), 8.49(1H, s), 8.84 (1H, d), 8.95 (1H, s); m/z: ES⁺ MH⁺ 509.

Intermediate 106:N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-(2-morpholin-4-ylethyl)-5-nitrobenzene-1,4-diamine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 311 mg, 0.75 mmol), N-methyl-2-morpholinoethanamine(130 mg, 0.90 mmol) and DIPEA (0.157 mL, 0.90 mmol) were dissolved inDMA (3 mL) and sealed into a microwave tube. The mixture was heated to140° C. for 0.75 h in the microwave then cooled to r.t. The mixture wasthen diluted with CH₃OH and purified by ion exchange chromatography,using an SCX column and eluting with 1:1 7N methanolic ammonia inCH₂Cl₂. Appropriate fractions were combined and concentrated in vacuo togive the title compound (429 mg, 106%) as an orange solid which was usedwithout further purification; ¹H NMR: 2.36 (4H, s), 2.54 (2H, m), 2.89(3H, s), 3.34 (2H, m), 3.49 (4H, m), 3.91 (3H, s), 6.81 (1H, s), 7.15(1H, m), 7.35 (1H, t), 8.16 (1H, s), 8.45 (2H, m), 8.76 (1H, s), 8.86(1H, d), 8.96 (1H, s); m/z: ES⁺ MH⁺ 539.

Intermediate 107:N⁴-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5-methoxy-N¹-methyl-N¹-[2-(4-methylpiperazin-1-yl)ethyl]benzene-1,2,4-triamine

A mixture ofN-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-[2-(4-methylpiperazin-1-yl)ethyl]-5-nitrobenzene-1,4-diamine(0.182 g, 0.33 mmol), iron (0.110 g, 1.98 mmol) and NH₄Cl (0.012 g, 0.23mmol) in EtOH (10 mL) and water (3.33 mL) was heated at reflux for 1.5h.The mixture was then cooled to r.t., filtered and concentrated in vacuo.Purification by ion exchange chromatography, using an SCX column andeluting with 1M methanolic ammonia provided a brown gum (162 mg) afterconcentration of appropriate fractions. Further purification by FCC,eluting with 2-7% 1M methanolic ammonia in CH₂Cl₂ gave the titlecompound (0.148 g, 86%) as a yellow gum; ¹H NMR: (CDCl₃) 2.28 (3H, s),2.32-2.63 (10H, m), 2.70 (3H, s), 2.98 (2H, t), 3.84 (3H, s), 4.05 (2H,d), 6.71 (1H, s), 6.95 (1H, td), 7.38 (1H, ddd), 7.52 (1H, d), 7.88 (1H,s), 8.36 (1H, s), 8.57 (1H, d), 8.65 (1H, d), 8.93 (1H, s); m/z: ES⁺ MH⁺522.57.

Intermediate 108:N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-[2-(4-methylpiperazin-1-yl)ethyl]-5-nitrobenzene-1,4-diamine

DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 20, 0.207 g, 0.5 mmol) andN-methyl-2-(4-methylpiperazin-1-yl)ethanamine (Intermediate 109, 0.079g, 0.50 mmol) in DMA (5 mL). The mixture was heated in a microwave at140° C. for 3 h. An additional portion ofN-methyl-2-(4-methylpiperazin-1-yl)ethanamine (8 mg, 0.05 mmol) wasadded and the mixture was heated in a microwave at 140° C. for a further1 h before being cooled to r.t. The mixture was then concentrated invacuo and the residue was dissolved in CH₃OH. Purification by ionexchange chromatography, using an SCX column and eluting with 1Mmethanolic ammonia provided crude material after concentration ofappropriate fractions in vacuo. Further purification by FCC, elutingwith 2-8% CH₃OH in CH₂Cl₂ gave the title compound (0.186 g, 67%) as anorange foam; ¹H NMR: (CDCl₃) 2.26 (3H, s), 2.32-2.45 (4H, m), 2.45-2.57(4H, m), 2.61 (2H, t), 2.89 (3H, s), 3.29 (2H, t), 3.98 (3H, s), 6.65(1H, s), 6.93-7.00 (1H, m), 7.38 (1H, ddd), 7.44 (1H, s), 8.40 (1H, s),8.49 (1H, d), 8.55 (1H, d), 8.91 (2H, d); m/z: ES⁺ MH⁺ 552.59.

Intermediate 109: N-Methyl-2-(4-methylpiperazin-1-yl)ethanamine

Ethyl carbonochloridate (8.14 mL, 85.14 mmol) was added dropwise toN-methyl-2-piperazin-1-ylethanamine (5.0 g, 38.7 mmol) and triethylamine(12.95 mL, 92.88 mmol) in THF (40 mL) at 0° C. over a period of 10minutes under N₂. The resulting mixture was allowed to warm to r.t. andstirred for 2 h. The resulting white suspension was filtered, and washedthrough with THF (2×20 mL). The filtrate was concentrated in vacuo andthe resulting residue was dissolved in EtOAc (75 mL). This solution waswashed with sat. Na₂CO₃ (50 mL). The aqueous wash solution was thenextracted with EtOAc (50 mL). The combined organic solutions were dried(MgSO₄) and concentrated in vacuo to give crude intermediate (10.55 g).This was dissolved in THF (60 mL) and cooled to 0° C. LiAlH₄ (101 mL,100.6 mmol, 1M in THF) was added dropwise under N₂. The resultingmixture was stirred at reflux overnight, then cooled to 0° C. andtreated successively (dropwise) with water (3.8 mL), 15% aq. NaOH (3.8mL) and water (11.4 mL) with rapid stirring. Diatomaceous earth(Celite™) and MgSO₄ were added and the mixture was filtered, washed withEtOAc and the filtrate was concentrated in vacuo to give a colourlessoil (3.35 g). The filtercake was washed with EtOAc (100 mL), heated to70° C. and then filtered. The filtrate was concentrated in vacuo to givea further batch (1.023 g) of the title compound. Total: 4.37 g, 72%; ¹HNMR: (CDCl₃) 2.28 (3H, s), 2.33-2.6 (13H, m), 2.67 (2H, t).

Intermediate 110:4-Methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine

A mixture ofN-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 111, 329 mg, 0.69 mmol), iron (233 mg, 4.17 mmol) andNH₄Cl (26.0 mg, 0.49 mmol) in ethanol (12 mL) and water (4 mL) wereheated at reflux for 3 h. The mixture was allowed to cool to r.t. andthen filtered. The filtrate was concentrated in vacuo. Purification byion exchange chromatography, using an SCX column and eluting with 0.7Mmethanolic ammonia gave a brown gum after concentration of appropriatefractions in vacuo. Further purification by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (287 mg, 93%) as alight brown gum; ¹H NMR: (CDCl₃) 2.37 (3H, br s), 2.59 (4H, s),2.92-2.99 (4H, m), 3.79-3.86 (5H, m), 3.87 (3H, s), 6.71 (1H, s), 7.01(1H, d), 7.27-7.34 (2H, m), 7.35-7.40 (1H, m), 7.57 (1H, s), 7.78 (1H,s), 8.17 (1H, s), 8.32 (1H, d), 8.47-8.53 (1H, m); m/z: ES⁺ MH⁺ 444.54.

Intermediate 111:N-[2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

1-Methylpiperazine (89 mg, 0.89 mmol),N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129 (which may be prepared by the method described forIntermediate 87), 350 mg, 0.89 mmol) and DIPEA (0.186 mL, 1.07 mmol)were suspended in DMA (6 mL) and sealed into a microwave tube. Thereaction was heated to 140° C. for 1 h in a microwave and then cooled tor.t. CH₃OH was added and an orange solid precipitated from solution. Thesolid was collected by filtration and was washed with CH₃OH and thendiethyl ether. The solid was then dried to give the title compound (339mg, 80%) as an orange solid; ¹H NMR: 2.26 (3H, s), 3.06-3.11 (4H, m),3.88 (3H, s), 3.99 (3H, s), 6.86 (1H, s), 7.13 (1H, t), 7.23-7.29 (2H,m), 7.53 (1H, d), 8.10 (1H, s), 8.32-8.38 (3H, m), 8.81 (1H, s);(signals for 4 protons were not observed and are likely to be obscuredunder the DMSO peak); m/z: ES⁺ MH⁺ 474.56.

Intermediate 112:N-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 113, 285 mg, 0.56 mmol), iron (188 mg, 3.37 mmol) andNH₄Cl (22.51 mg, 0.42 mmol) in ethanol (9 mL) and water (3 mL) washeated at reflux for 2 h. The mixture was then cooled and filteredthrough diatomaceous earth (Celite™). The filtrate was concentrated invacuo and the resulting residue was dissolved in CH₂Cl₂. This solutionwas washed with brine, dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 1-20% 7N methanolic ammonia in CH₂Cl₂gave the title compound (263 mg, 98%) as a brown dry film; ¹H NMR:(CDCl₃) 2.21 (6H, s), 3.08-3.18 (1H, m), 3.30 (2H, br s), 3.58 (2H, t),3.86 (3H, s), 3.88 (3H, s), 3.93 (2H, t), 6.38 (1H, s), 7.2-7.42 (3H, m,partially obscured by chloroform signal), 7.50 (1H, s), 7.99 (1H, s),8.20 (1H, s), 8.31 (1H, s), 8.63 (1H, d); m/z: ES⁺ MH⁺ 478.

Intermediate 113:5-Chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

DIPEA (0.408 mL, 2.33 mmol) was added to a mixture of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine.0.8 toluene-4-sulfonic acid salt (Intermediate 87, 330 mg, 0.58 mmol) inDMA (3 mL). N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate26, 121 mg, 0.70 mmol) was then added in one portion. The mixture washeated in a microwave at 100° C. for 0.5 h then the mixture was cooledand diluted with CH₃OH and absorbed onto an SCX column. The column waswashed with CH₃OH and eluted with 1:1 methanolic ammonia in CH₂Cl₂.Appropriate fractions were concentrated in vacuo. Further purificationby FCC, eluting with 1-10% CH₃OH in CH₂Cl₂ gave the title compound (295mg, 100%) as a brown gum; ¹H NMR: (CDCl₃) 2.18 (6H, s), 3.13-3.24 (1H,m), 3.67-3.75 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.13 (2H, t), 6.04(1H, s), 7.21-7.29 (1H, m, partially obscured by chloroform signal),7.29-7.41 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.46 (1H, d), 9.05 (1H,s); m/z: ES⁺ MH⁺ 508.

Intermediate 114:4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 115, 210 mg, 0.43 mmol), iron (144 mg, 2.58 mmol) andNH₄Cl (16.13 mg, 0.30 mmol) in ethanol (6 mL) and water (2 mL) wereheated at reflux for 2 h. The crude mixture was purified by ion exchangechromatography, using an SCX column and eluting with 7M methanolicammonia. Appropriate fractions were combined and concentrated in vacuoonto silica. Further purification by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ gave a brown foam after concentration ofappropriate fractions in vacuo. Further purification by ion exchangechromatography, using an SCX column and eluting with 7M methanolicammonia provided material that was concentrated in vacuo onto silica.Further purification by FCC, eluting with 0-4% CH₃OH in CH₂Cl₂ gave thetitle compound (135 mg, 69%) as a brown foam; ¹H NMR: 2.11 (6H, s), 2.35(3H, s), 3.04 (1H, p), 3.44 (2H, t), 3.89 (3H, s), 3.92 (2H, s),3.9-3.97 (2H, m), 6.28 (1H, s), 7.12 (1H, dd), 7.2-7.26 (1H, m), 7.28(1H, s), 7.48 (1H, d), 7.55 (1H, s), 8.00 (1H, s), 8.15 (1H, s), 8.43(1H, d); m/z: ES⁺ MH⁺ 458.31.

Intermediate 115:N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine

N,N-dimethylazetidin-3-amine (Intermediate 26, 113 mg, 0.65 mmol) wasadded to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-amine(Intermediate 79, 250 mg, 0.61 mmol) and DIPEA (0.374 mL, 2.15 mmol) in2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at140° C. for 1 h. The cooled mixture was purified by ion exchangechromatography, using an SCX column and eluting with 7M methanolicammonia. Appropriate fractions were combined and concentrated in vacuoonto silica. Further purification by FCC, eluting with 0-4% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (213 mg, 71%) as anorange foam; ¹H NMR: 2.13 (6H, s), 2.37 (3H, s), 3.09-3.16 (1H, m), 3.72(2H, dd), 3.89 (3H, s), 3.93 (3H, s), 4-4.08 (2H, m), 6.27 (1H, s), 7.04(1H, t), 7.20-7.26 (1H, m), 7.49 (1H, d), 7.90 (1H, s), 8.03 (1H, s),8.23 (1H, s), 8.35 (1H, d), 8.46 (1H, s); m/z: ES⁺ MH⁺ 488.63.

Intermediate 116:4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 117, 160 mg, 0.34 mmol), iron (113 mg, 2.03 mmol) andNH₄Cl (13.56 mg, 0.25 mmol) in ethanol (5 mL) and water (1.67 mL) washeated at reflux for 2 h. The cooled mixture was purified by ionexchange chromatography, using an SCX column and eluting with 1:1 7Mmethanolic ammonia in CH₂Cl₂. Appropriate fractions were combined andconcentrated in vacuo. Further purification by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (120 mg, 80%) as abrown gum; m/z: ES⁺ MH⁺ 444.61.

Intermediate 117:N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 79 mg,0.46 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129 (which may be prepared by the method described forIntermediate 87), 150 mg, 0.38 mmol) and DIPEA (0.264 mL, 1.53 mmol) in2,2,2-trifluoroethanol (3 mL). The mixture was heated at 140° C. in amicrowave for 1 h. The mixture was then purified directly by ionexchange chromatography, using an SCX column (50g) and eluting with 1:17M methanolic ammonia in CH₂Cl₂. Concentration of appropriate fractionsin vacuo gave a brick red solid. This solid was suspended in CH₃OH andthe solid was collected by filtration, washed with CH₃OH (10 mL) anddried in vacuo to give the title compound (160 mg, 89%) as a red solid;m/z: ES⁺ MH⁺ 474.61.

Intermediate 118:N-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine

A mixture of5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 119, 347 mg, 0.70 mmol), iron (235 mg, 4.22 mmol) andNH₄Cl (26.3 mg, 0.49 mmol) in ethanol (9 mL) and water (3 mL) was heatedat reflux for 1 h. The mixture was then purified by ion exchangechromatography, using an SCX column and eluting with 7M methanolicammonia. Appropriate fractions were combined and concentrated in vacuoonto silica. Further purification by FCC, eluting with 0-5% 7Mmethanolic ammonia in CH₂Cl₂ gave the title compound (323 mg, 99%) as atan solid; ¹H NMR: 2.12 (6H, s), 3.06 (1H, p), 3.48 (2H, t), 3.68 (3H,s), 3.92-4.02 (4H, m), 6.28 (1H, s), 6.91 (1H, s), 7.04 (1H, dd),7.12-7.19 (1H, m), 7.44 (1H, d), 8.14 (1H, s), 8.28 (1H, s), 8.30 (1H,d), 8.46 (1H, s), 11.77 (1H, s); m/z: ES⁺ MH⁺ 464.21.

Intermediate 119:5-Chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine

N,N-dimethylazetidin-3-amine (Intermediate 26, 144 mg, 0.83 mmol) wasadded to a suspension of5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 76, 312 mg, 0.75 mmol) and DIPEA (0.460 mL, 2.64 mmol) in2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at140° C. for 1 h. The cooled mixture was purified by ion exchangechromatography, using an SCX column and eluting with 7M methanolicammonia. Appropriate fractions were combined and concentrated in vacuoonto silica. Further purification by FCC, eluting with 0-4% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (347 mg, 93%) as anorange solid after trituration with diethyl ether; ¹H NMR: 2.14 (6H, s),3.09-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.01-4.11 (2H, m), 6.28(1H, s), 6.98 (1H, t), 7.13-7.20 (1H, m), 7.46 (1H, d), 8.15 (1H, s),8.23 (1H, d), 8.37 (1H, s), 8.47 (1H, s), 8.49 (1H, s), 11.84 (1H, s);m/z: ES⁺ MH⁺ 494.16.

Intermediate 120:2-({5-Amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile

A mixture ofN-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine(Intermediate 18, 250 mg, 0.52 mmol), zinc cyanide (36.8 mg, 0.31 mmol),zinc powder (3.41 mg, 0.05 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (‘XPhos’49.8 mg, 0.10 mmol) was stirred in DMA (2 mL) and purged with N₂ for0.25h. Tris(dibenzylidene-acetone)dipalladium(0) (47.8 mg, 0.05 mmol)was then added and the mixture was heated at 95° C. for 2 h. The cooledmixture was then absorbed onto an SCX column, washed with CH₃OH andeluted with 7M methanolic ammonia solution. Appropriate fractions werecombined and concentrated in vacuo. The resulting residue was suspendedin CH₃OH then the mixture was filtered. The collected solid was dried onthe filter to give the title compound (160 mg, 65%) as a tan powder; ¹HNMR: (100° C.) 1.78-1.92 (1H, m), 2.00-2.15 (1H, m), 2.26 (6H, s),2.95-3.02 (1H, m), 3.02-3.07 (1H, m), 3.07-3.13 (1H, m), 3.16-3.27 (2H,m), 3.68 (3H, s), 6.74 (1H, s), 6.95 (1H, s), 7.13 (1H, td), 7.33-7.43(1H, m), 8.37 (1H, d), 8.64 (1H, s), 8.77 (1H, dt), 8.84 (1H, s), 8.91(1H, s); m/z: ES⁺ MH⁺ 470.60.

Intermediate 121:2-{[5-Amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile

N⁴-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine(Intermediate 33, 120 mg, 0.26 mmol), dicyanozinc (18.11 mg, 0.15 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (24.50 mg,0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.5 mg, 0.03mmol) and zinc powder (1.681 mg, 0.03 mmol) were suspended in degassedDMA (1.1 mL) and sealed into a microwave tube. The mixture was thenheated to 95° C. for 1 h in a microwave. The cooled mixture was thendiluted with EtOAc (50 mL) and washed with sat. NaHCO₃ (20 mL), water(20 mL), and sat. brine (10 mL). The organic solution was thenconcentrated in vacuo. Purification by FCC, eluting with 0-20% CH₃OH inCH₂Cl₂ gave the title compound (36 mg, 31%) as a yellow gum; ¹H NMR:(CDCl₃) 2.41 (6H, s), 2.60 (2H, s), 2.72 (3H, s), 3.07 (2H, t), 3.86(3H, s), 6.72 (1H, s), 7.02 (1H, t), 7.41-7.53 (1H, m), 7.80 (2H, d),8.60 (2H, d), 8.70 (1H, d), 9.09 (1H, s); m/z: ES⁺ MH⁺ 458.30.

Intermediate 122:2-{[5-Amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-phenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile

N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine(Intermediate 24, 297 mg, 0.64 mmol),tris(dibenzylidene-acetone)dipalladium(0) (14.62 mg, 0.02 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (‘XPhos’,30.5 mg, 0.06 mmol), and dicyanozinc (45.0 mg, 0.38 mmol) were placed ina microwave tube under N₂. Poly(methylhydrosiloxane) (12 mg, 0.06 mmol)was then added in degassed DMA (1.92 mL). The resulting mixture was thenheated at 120° C. for 2 h in a microwave. The crude mixture was loadedon to a SCX column. The column was flushed with water followed byCH₃OH/CH₂Cl₂. The desired product was eluted from the column using 7Mmethanolic ammonia in CH₂Cl₂ and pure fractions were combined andconcentrated in vacuo. The residue was dissolved in CH₃OH/CH₂Cl₂ andallowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE(available from Polymer Laboratories) under gravity. The resultingsolution was concentrated in vacuo. Purification by FCC, eluting with0-5% CH₃OH in CH₂Cl₂ gave the title compound (139 mg, 48%) as a brownsolid after trituration with diethyl ether; ¹H NMR: (100° C.) 2.18 (6H,s), 3.17 (1H, t), 3.60 (2H, t), 3.69 (3H, s), 3.87 (2H, br s), 4.00 (2H,t), 6.32 (1H, s), 6.86 (1H, s), 7.11 (1H, t), 7.34-7.46 (1H, m), 8.34(1H, d), 8.61 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.90 (1H, s); m/z:ES⁺ MH⁺ 456.23.

Intermediate 123:4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 124, 256 mg, 0.51 mmol), iron powder (172 mg, 3.07 mmol)and NH₄Cl (19.19 mg, 0.36 mmol) were heated in ethanol (3 mL) and water(1 mL) at reflux for 18 h. The crude mixture was then purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M methanolic ammonia and concentrated invacuo. Further purification by FCC, eluting with 0-5% 7N methanolicammonia in CH₂Cl₂ gave the title compound (198 mg, 82%) as a yellowfoam; ¹H NMR (CDCl₃) 1.78 (1H, td), 2.07-2.13 (1H, m), 2.15 (1H, dd),2.29 (3H, s), 2.47 (1H, dd), 2.57-2.65 (2H, m), 2.82-2.95 (2H, m), 3.45(1H, dt), 3.85 (3H, s), 3.88 (3H, s), 4.07 (1H, ddd), 6.74 (1H, s), 7.01(1H, d), 7.27-7.35 (2H, m), 7.38 (1H, dd), 7.55 (1H, s), 7.79 (1H, s),8.14 (1H, s), 8.33 (1H, d), 8.45-8.52 (1H, m); m/z: ES⁺ MH⁺ 470.29.

Intermediate 124:N-[4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

DIPEA (0.411 mL, 2.36 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129, 425 mg, 0.94 mmol) and(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole(Intermediate 37, 250 mg, 1.98 mmol) in 2,2,2-trifluoroethanol (4 mL).The mixture was heated in a microwave at 140° C. for 1 h. The cooledmixture was then purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7Mmethanolic ammonia and concentrated in vacuo. Further purification byFCC, eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave impure titlecompound (396 mg, 84%) as an orange/red solid. This solid was dissolvedin the minimum amount of CH₂Cl₂ and the resulting solution wastriturated with methanol. The resulting solid was collected byfiltration to give the title compound (272 mg, 58%) as a red solid whichwas used without further purification; ¹H NMR: 1.86 (1H, dd), 1.94-2.06(1H, m), 2.12 (3H, s), 2.23 (1H, dd), 2.36-2.45 (2H, m), 2.52-2.58 (1H,m) partially obscured by DMSO peak, 2.91-3.04 (1H, m), 3.18 (1H, t),3.49 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 4.40 (1H, t), 6.61 (1H, s),7.11 (1H, t), 7.18 (1H, d), 7.24 (1H, t), 7.51 (1H, d), 8.02 (1H, s),8.27-8.31 (2H, m), 8.34 (1H, d), 8.51 (1H, s); m/z: ES⁺ MH⁺ 500.17.

Intermediate 125:N¹-(2-Dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

A mixture ofN′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,4-diamine(Intermediate 126, 3.7 g, 7.93 mmol), iron (2.66 g, 47.58 mmol) andNH₄Cl (0.318 g, 5.95 mmol) was heated in ethanol (120 mL) and water (40mL) at reflux for 2.5h. The mixture was then cooled, filtered andconcentrated. The solids were triturated in 5% CH₃OH/CH₂Cl₂ (100 mL) for15 minutes and then filtered. The filtrate was combined with theconcentrated, filtered reaction mixture, washed with brine, dried(Na₂SO₄) and concentrated in vacuo. Purification by FCC, eluting with0-2.5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (2.50 g,72%) as a brown gum; ¹H NMR (CDCl₃): 1.90-1.99 (2H, m), 2.04-2.13 (2H,m), 2.25 (6H, s), 2.37-2.42 (2H, m), 2.67 (3H, s), 2.92-2.98 (2H, m),3.25 (2H, t), 3.83 (3H, s), 4.00 (2H, s), 4.21 (2H, t), 6.70 (1H, s),6.79 (1H, d), 7.48 (1H, s), 7.97 (2H, d), 8.30 (1H, d); m/z: ES⁺ MH⁺437.39.

Intermediate 126:N′-(2-Dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,4-diamine

A mixture ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-c]pyridin-3-yl)pyrimidin-2-amine(Intermediate 127, 3.0 g, 7.81 mmol),N,N′,N′-trimethylethane-1,2-diamine (1.190 mL, 9.37 mmol) and DIPEA(1.620 mL, 9.37 mmol) in DMA (45 mL) was heated at 100° C. for 1.5h. Themixture was then cooled and absorbed onto an SCX column, washed withMeOH and eluted with methanolic ammonia. Fractions that containeddesired product were concentrated in vacuo and the resulting residue wasdissolved in EtOAc. This solution was washed twice with brine, dried(Na₂SO₄) and concentrated in vacuo to give the title compound (3.70 g,102%) as an orange oil; ¹H NMR (CDCl₃): 1.90-1.98 (2H, m), 2.04-2.12(2H, m), 2.26 (6H, s), 2.51-2.60 (2H, m), 2.87 (3H, s), 3.21-3.30 (4H,m), 3.96 (3H, s), 4.20 (2H, t), 6.67 (1H, s), 6.88 (1H, d), 7.43 (1H,s), 7.95 (1H, s), 8.31 (1H, d), 9.00 (1H, s); m/z: ES⁺ MH⁺ 467.63.

Intermediate 127:N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

A mixture of3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(Intermediate 128, 3.6857 g, 15.70 mmol),4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 2.92 g, 15.70 mmol)and p-toluenesulfonic acid hydrate (3.29 g, 17.28 mmol) in 2-pentanol(100 mL) was stirred at 85° C. under an atmosphere of N₂ for 1.5h. Themixture was then concentrated in vacuo and the resulting reside wasdissolved in CH₂Cl₂ (250 mL). This solution was washed with sat. NaHCO₃(2×100 mL), water (100 mL), and sat. brine (100 mL). The organicsolution was concentrated in vacuo to give crude product. Purificationby FCC, eluting with 0-10% CH₃OH in CH₂Cl₂ provided an orange solid.This material was triturated with CH₃OH to give a solid which wascollected by filtration and dried in vacuo to give the title compound(2.26 g, 37%) as a yellow solid; ¹H NMR: 1.75-1.86 (2H, m), 1.92-2.04(2H, m), 3.09 (2H, t), 4.02 (3H, s), 4.12 (2H, t), 7.13 (1H, d), 7.35(1H, d), 8.14 (1H, s), 8.25 (1H, s), 8.42 (1H, d), 9.02 (1H, d); m/z:ES⁺ MH⁺ 385.

Intermediate 128:3-(2-Chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridine

Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(1.284 g, 1.81 mmol) was added in one portion to3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(9 g, 36.27 mmol), 2,4-dichloropyrimidine (5.40 g, 36.27 mmol) and 2MNa₂CO₃ solution (39.9 mL, 79.80 mmol) in dimethoxyethane (250 mL) underan atmosphere of N₂. The resulting mixture was stirred at 85° C. for 4h. and then allowed to cool to r.t. The mixture was then concentrated invacuo and the residue was dissolved in CH₂Cl₂ (500 mL). This solutionwas washed with water (200 mL) and then sat. brine (200 mL). The organicsolution was concentrated in vacuo. Purification by FCC, eluting with0-10% CH₃OH in CH₂Cl₂ gave the title compound (7.91 g, 93%) as a orangeoil which solidified on standing; ¹H NMR: 1.86 (2H, dt), 1.93-2.00 (2H,m), 3.11 (2H, t), 4.13 (2H, t), 7.68 (1H, d), 8.18 (1H, s), 8.57 (1H,d); m/z: ES⁺ MH⁺ 235.

Intermediate 129:N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine

p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in oneportion to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole(Intermediate 130, 24.27 g, 99.58 mmol) and4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 18.54 g, 99.58 mmol)in 2-pentanol (500 mL). The resulting mixture was stirred at 105° C. for2.5h. and then cooled to r.t. The resulting precipitate was collected byfiltration, washed with 2-pentanol (50 mL) and dried under vacuum togive some of the desired product as a yellow solid. The filtrate wascooled and the resulting precipitate was collected by filtration andwashed with 2-pentanol (10 mL). The two crops of product were combinedand triturated with CH₃CN to give a solid which was collected byfiltration and dried under vacuum to give the title compound (37.4 g,95%) as a yellow solid; ¹H NMR: 3.92 (3H, s), 4.01 (3H, s), 7.13 (1H,dd), 7.27-7.36 (1H, m), 7.40-7.51 (2H, m), 7.59 (1H, d), 8.26 (1H, t),8.35 (1H, d), 8.61 (1H, s), 8.85 (1H, d), 9.46 (1H, s); m/z: ES⁻ M⁻ 392.

Intermediate 130: 3-(2-Chloropyrimidin-4-yl)-1-methylindole

NaH (1.707 g, 42.68 mmol, 40% dispersion in mineral oil) was added insmall portions to a cooled (0° C.) mixture of3-(2-chloropyrimidin-4-yl)-1H-indole (Intermediate 131, 8.168 g, 35.57mmol) in THF (250 mL). The resulting mixture was stirred at 0° C. for0.5 h and then CH₃I (2.67 mL, 42.68 mmol) was added and the mixturestirred at 0° C. for a further 3h. The reaction was quenched by theaddition of sat. NaHCO₃ (25 mL). The mixture was then diluted with EtOAc(100 mL), and the resulting solution was washed with sat. NaHCO₃ (50mL), water (50 mL) and sat. brine (50 mL). The organic solution was thenconcentrated in vacuo. Purification by FCC, eluting with 0-20% CH₃OH inCH₂Cl₂ gave the title compound (8.35 g, 96%) as a pale yellow solid; ¹HNMR: 3.90 (3H, s), 7.30 (2H, pd), 7.54-7.60 (1H, m), 7.82 (1H, d),8.38-8.44 (1H, m), 8.49 (1H, s), 8.53 (1H, d); m/z: ES⁺ MH⁺ 1244.

Intermediate 130: 3-(2-Chloropyrimidin-4-yl)-1-methylindole (Alternativesynthesis)

AlCl₃ (197 g, 1.477 mol) was added portionwise to a solution of2,4-dichloro-pyrimidine (200 g, 1342 mmol) in dimethoxyethane (2 L)while maintaining the temperature below 30° C., and the mixture wasstirred for 10 minutes. 1-Methylindole (0.172 L, 1.342 mol) was thenadded and the mixture was heated to 80° C. for 2 h and then left to coolovernight. The mixture was then poured into stirring water (20 L) andthen was stirred for a further 1h. The mixture was then filtered and theresulting solid was washed with water (3 L). The solid was thenair-dried for 16 h, to give a pink solid (315g). This solid was thenstirred in refluxing CH₃CN (6.3 L) for 1.5 h at which point water (630mL) was added. The mixture was then allowed to cool to r.t. and wasstirred for 18 h. The mixture was then stirred at 5° C. for 0.5 h thenthe resulting solid was collected by filtration. The solid was thenwashed with cold 10% CH₃CN/water (2×μL) and then dried to give the titlecompound (220g, 67%) as a cream solid.

Intermediate 131: 3-(2-Chloropyrimidin-4-yl)-1H-indole

CH₃MgBr (3M in diethyl ether, 22.68 mL, 68.03 mmol) was added dropwiseover a period of 10 minutes to a stirred solution of 1H-indole (7.97 g,68.03 mmol) in 1,2-dichloroethane (250 mL) at 0° C. under an atmosphereof N₂. The resulting solution was stirred for 15 minutes and then2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion.The resulting solution was allowed to warm to r.t. and was stirred for afurther 16h. The reaction was quenched by the addition of CH₃OH (25 mL)then the mixture was concentrated in vacuo and absorbed onto silica.Purification by FCC, eluting with 0-20% CH₃OH in CH₂Cl₂ gave the titlecompound (7.17 g, 46%) as a yellow solid; ¹H NMR: 7.20-7.28 (2H, m),7.49-7.53 (1H, m), 7.91 (1H, d), 8.42 (1H, dd), 8.50 (1H, d), 8.53 (1H,d), 12.06 (1H, s); m/z: ES⁺ MH⁺ 230.

Intermediate 132:4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]-pyrrol-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-{4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 133, 400 mg, 0.82 mmol), iron (273 mg, 4.89 mmol) andNH₄Cl (30.5 mg, 0.57 mmol) in ethanol (12 mL) and water (4 mL) washeated at reflux for 4 h and then stirred at r.t.overnight.Part-purification by ion exchange chromatography, using an SCX column,eluting with 7M methanolic ammonia provided crude material that wasconcentrated in vacuo onto silica. Purification by FCC, eluting with0-5% 7N methanolic ammonia in CH₂Cl₂ provided impure product as a browngum. Further purification by FCC, eluting with 0-2% 7N methanolicammonia in CH₂Cl₂ provided the title compound (123 mg, 33%) as a browngum; m/z: ES⁺ MH⁺ 461.26.

Intermediate 133:N-{4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]-pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

DIPEA (0.583 mL, 3.35 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 127, 515 mg, 1.34 mmol) and(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole(Intermediate 37, 186 mg, 1.47 mmol) in 2,2,2-trifluoroethanol (5 mL)and the mixture was heated in a microwave at 140° C. for 1 h. Aftercooling, the mixture was part-purified by ion exchange chromatography,using an SCX column, eluting with 7M methanolic ammonia, and thenconcentrated in vacuo onto silica. Purification by FCC, eluting with0-5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (400 mg,61%) as an orange/red foam; ¹H NMR (CDCl₃): 1.87 (1H, dd), 1.90-1.98(2H, m), 2.03-2.14 (3H, m), 2.20 (3H, s), 2.28 (1H, dd), 2.45 (2H, ddd),2.60-2.67 (1H, m), 2.97-3.07 (1H, m), 3.18-3.34 (3H, m), 3.48-3.58 (1H,m), 3.96 (3H, s), 4.20 (2H, t), 4.40 (1H, ddd), 6.43 (1H, s), 6.86 (1H,d), 7.35 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.92 (1H, s); m/z: ES⁺ MH⁺491.15.

Intermediate 134:4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 135, 198.7 mg, 0.42 mmol), iron (139 mg, 2.49 mmol) andNH₄Cl (15.6 mg, 0.29 mmol) in ethanol (15 mL) and water (5 mL) washeated at reflux for 2.5h. The mixture was then allowed to cool to r.t.,filtered and concentrated in vacuo. Part-purification by ion exchangechromatography, using an SCX column, eluting with 0.7M methanolicammonia provided crude material as a yellow gum. Further purification byFCC, eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (159 mg, 85%) as a brown foam; ¹H NMR (CDCl₃): 1.83-1.97 (3H,m), 2.05-2.17 (3H, m), 2.29 (6H, s), 2.83-2.91 (1H, m), 2.98-3.08 (2H,m), 3.15-3.20 (2H, m), 3.24 (2H, t), 3.69 (2H, s), 3.83 (3H, s), 4.20(2H, t), 6.69 (1H, s), 6.78 (1H, d), 7.45 (1H, s), 7.97 (2H, d), 8.29(1H, d); m/z: ES⁺ MH⁺ 449.65.

Intermediate 135:N-{4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

(3R)—N,N-Dimethylpyrrolidin-3-amine (64 mg, 0.56 mmol),N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 127, 267 mg, 0.53 mmol) and DIPEA (0.186 mL, 1.07 mmol)were suspended in DMA (2 mL), sealed into a microwave tube and thenheated to 140° C. for 1 h in a microwave reactor. After cooling to r.t.the mixture was part-purified by ion exchange chromatography, using anSCX column. The column was first washed with CH₃OH and then eluted with0.7M methanolic ammonia. Clean fractions were concentrated in vacuo togive crude material as an orange gum. Purification by FCC, eluting with0-5% 7N methanolic ammonia in CH₂Cl₂ gave the title compound (201 mg,79%) as a orange gum; ¹H NMR (CDCl₃): 1.89-1.98 (3H, m), 2.05-2.12 (2H,m), 2.16-2.23 (1H, m), 2.30 (6H, s), 2.78-2.87 (1H, m), 3.14-3.37 (5H,m), 3.54 (1H, td), 3.96 (3H, s), 4.20 (2H, t), 6.34 (1H, s), 6.85 (1H,d), 7.33 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.95 (1H, s); m/z: ES⁺ MH⁺479.60.

Intermediate 136:4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg,0.03 mmol) was added to a solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(139 mg, 0.62 mmol),4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 137, 215 mg, 0.52 mmol), and K₃PO₄ (220 mg, 1.04 mmol) in1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior touse). The mixture was then heated at 100° C. for 1 h and thenconcentrated in vacuo. The resulting residue was dissolved in EtOAc andthis solution was washed three times with water, then with brine. Thesolution was then dried (MgSO₄) and concentrated in vacuo. Purificationby FCC, eluting with 0-10% methanolic ammonia in CH₂Cl₂ gave the titlecompound (160 mg, 72%) as a tan solid after trituration with diethylether; ¹H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s),2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75(3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s),7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d);m/z: ES⁺ MH⁺ 432.72.

Intermediate 137:4-Bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 138, 944 mg, 2.12 mmol), iron (710 mg, 12.7 mmol) andNH₄Cl (85 mg, 1.59 mmol) were heated in ethanol (40 mL) and water (13mL) at reflux for 1.5h. The mixture was then cooled and filtered. Theresidue was triturated in 10% CH₃OH in CH₂Cl₂ (30 mL) for 15 minutes andthen filtered. The residues were triturated again with 10% CH₃OH inCH₂Cl₂ (30 mL) and filtered. The combined filtrates were washed withbrine, dried (MgSO₄) and concentrated in vacuo. Purification by FCC,eluting with 0-5% CH₃OH in CH₂Cl₂ gave the title compound (814 mg, 92%)as a brown solid after trituration with diethyl ether; ¹H NMR: 1.80-1.87(2H, m), 1.96-2.03 (2H, m), 3.13 (2H, t), 3.77 (3H, s), 4.12 (2H, t),4.82 (2H, s), 7.02 (1H, s), 7.05 (1H, d), 7.75 (1H, s), 7.77 (1H, s),8.10 (1H, s), 8.34 (1H, d); m/z: ES⁺ MH⁺ 415/417.

Intermediate 138:N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

A solution of3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(Intermediate 128, 0.893 g, 3.80 mmol), p-toluene sulphonic acidmonohydrate (1.034 g, 5.43 mmol) and 4-bromo-2-methoxy-5-nitroaniline(Intermediate 4, 0.895 g, 3.62 mmol) in 2-pentanol (35 mL) was heated atreflux for 16 h under an atmosphere of N₂. The mixture was then allowedto cool, and was concentrated in vacuo. The resulting residue wastriturated in CH₃CN until a yellow precipitate formed. The solid wascollected by filtration and was washed with diethyl ether. The solidthen was dissolved in 10% CH₃OH in CH₂Cl₂ and the resulting solution waswashed twice with sat. NaHCO₃, then with water. The solution was thendried (MgSO₄) and concentrated in vacuo. The resulting residue wastriturated with CH₃CN, the resulting solid collected by filtration,washed with diethyl ether, and then air dried to give the title compound(0.946 g, 59%) as a yellow solid; ¹H NMR: 1.80-1.87 (2H, m), 1.96-2.03(2H, m), 3.11 (2H, t), 4.04 (3H, s), 4.13 (2H, t), 7.17 (1H, d), 7.50(1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.45 (1H, d), 9.10 (1H, s); m/z:ES⁺ MH⁺ 445/447.

Intermediate 139:4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 140, 130 mg, 0.28 mmol), iron (94 mg, 1.68 mmol) and NH₄Cl(10.48 mg, 0.20 mmol) in ethanol (12 mL) and water (4 mL) was heated atreflux for 2.5h. The mixture was allowed to cool to r.t., filtered andconcentrated in vacuo. Part-purification by ion exchange chromatography,using an SCX column, eluting with 0.7M methanolic ammonia provided crudematerial as a brown gum. Further purification by FCC, eluting with 0-5%7N methanolic ammonia in CH₂Cl₂ gave the title compound (111 mg, 91%) asa brown gum; ¹H NMR (CDCl₃): 1.90-1.98 (2H, m), 2.04-2.12 (2H, m), 2.20(6H, s), 3.08-3.16 (1H, m), 3.23 (2H, t), 3.35 (1H, s), 3.56 (2H, t),3.84 (3H, s), 3.93 (2H, dd), 4.20 (2H, t), 6.37 (1H, s), 6.76 (1H, d),7.35 (1H, s), 7.87 (1H, s), 7.95 (1H, s), 8.28 (1H, d); m/z: ES⁺ MH⁺435.58.

Intermediate 140:N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 109 mg,0.63 mmol),N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 127, 300 mg, 0.60 mmol), DIPEA (0.386 mL, 2.22 mmol) andDMA (4 mL) was sealed into a microwave tube and heated to 140° C. for 1h in the microwave reactor. After cooling, to r.t., the mixture waspart-purified by ion exchange chromatography, using an SCX column. Thecolumn was first washed with CH₃OH and then the desired product waseluted from the column using 0.7M methanolic ammonia. Clean fractionswere concentrated in vacuo to give an orange gum. Further purificationby FCC, eluting with 0-5% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (140 mg, 50%) as an orange solid; ¹H NMR (CDCl₃): 1.90-1.98(2H, m), 2.05-2.12 (2H, m), 2.20 (6H, s), 3.15-3.23 (1H, m), 3.28 (2H,t), 3.69 (2H, dd), 3.96 (3H, s), 4.18 (4H, dt), 6.03 (1H, s), 6.87 (1H,d), 7.35 (1H, s), 7.97 (1H, s), 8.31 (1H, d), 9.02 (1H, s); m/z: ES⁺ MH⁺465.61.

Intermediate 141:4-Methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 142, 320 mg, 0.65 mmol), iron (219 mg, 3.91 mmol) andNH₄Cl (26.2 mg, 0.49 mmol) were heated at reflux in ethanol (18 mL) andwater (6 mL) for 4 h. The mixture was then cooled, filtered andconcentrated in vacuo. The resulting residue was triturated in 10% CH₃OHin CH₂Cl₂ (15 mL) for 15 minutes and the mixture was then filtered. Theresidues were re-triturated with 10% CH₃OH in CH₂Cl₂ (15 mL) and themixture was then filtered. The combined filtrates were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. Purification by FCC,eluting with 2% 7N methanolic ammonia in CH₂Cl₂ gave the title compound(251 mg, 84%) as a brown gum which crystallised on standing; ¹H NMR:1.64-1.76 (2H, m), 1.75-1.87 (2H, m), 1.91-2.03 (2H, m), 2.08 (2H, dd),2.39 (3H, s), 2.63 (2H, t), 3.06 (2H, t), 3.56 (2H, d), 3.72 (3H, s),3.82 (2H, d), 4.01 (2H, s), 4.10 (2H, t), 6.25 (1H, s), 6.91 (1H, d),7.21 (1H, s), 7.67 (1H, s), 8.04 (1H, s), 8.23 (1H, d); m/z: ES⁺ MH⁺461.37.

Intermediate 142:N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine(Intermediate 127, 300 mg, 0.78 mmol),8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 118 mg, 0.94 mmol)and DIPEA (0.162 mL, 0.94 mmol) were heated at 100° C. in DMA (4 mL) for1.75h. The mixture was then absorbed onto an SCX column, then the columnwas washed with CH₃OH and then eluted with 1:1 7M methanolic ammonia inCH₂Cl₂. Fractions that contained the desired product were combined andconcentrated in vacuo. Purification by FCC, eluting with 2.5% 7Nmethanolic ammonia in CH₂Cl₂ gave the title compound (321 mg, 84%) as anorange foam; ¹H NMR: 1.62-1.74 (2H, m), 1.74-1.85 (2H, m), 1.91-2.00(2H, m), 2.00-2.06 (2H, m), 2.38 (3H, s), 2.65 (2H, t), 3.03 (2H, t),3.71 (2H, d), 3.95 (3H, s), 4.04-4.15 (4H, m), 6.27 (1H, s), 7.01 (1H,d), 8.01 (1H, s), 8.09 (1H, s), 8.33 (1H, d), 8.54 (1H, s); m/z: ES′ MH⁺491.6.

Intermediate 143:4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.74 mg,0.03 mmol) was added to a solution containing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(139 mg, 0.62 mmol),4-bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine(Intermediate 144, 220 mg, 0.52 mmol), and K₃PO₄ (220 mg, 1.04 mmol) in1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior touse). The mixture was heated at 100° C. for 1 h and then concentrated invacuo. The resulting residue was dissolved in EtOAc. This solution waswashed with water (×3), brine, and was then dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-10%methanolic ammonia in CH₂Cl₂ gave the title compound (191 mg, 84%) as atan solid after trituration with diethyl ether; ¹H NMR: 2.31 (3H, s),2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89(3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22(2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 (1H, s), 7.81 (1H, s),8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES⁺ MH⁺ 441.57.

Intermediate 144:4-Bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-benzene-1,3-diamine

N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 145, 1.074g, 2.36 mmol), iron (0.792 g, 14.19 mmol) andNH₄Cl (95 mg, 1.77 mmol) were heated at reflux in ethanol (39 mL) andwater (13 mL) for 1.5h. The mixture was then cooled and concentrated invacuo. The resulting residue was triturated in 10% CH₃OH in CH₂Cl₂ (30mL) for 15 minutes and the mixture was then filtered. The residues weretriturated again with 10% CH₃OH in CH₂Cl₂ (30 mL) and the mixture thenfiltered. The combined filtrates were washed with brine, dried (MgSO₄)and concentrated in vacuo. Purification by FCC, eluting with CH₂Cl₂ gavethe title compound (0.937 g, 93%) as a cream foam; ¹H NMR: 3.79 (3H, s),3.89 (3H, s), 4.86 (2H, s), 7.06 (1H, s), 7.18-7.30 (3H, m), 7.54 (1H,d), 7.83 (1H, s), 7.87 (1H, s), 8.33 (1H, d), 8.35 (1H, s), 8.43 (1H,d); m/z: ES⁺ MH⁺ 424/426.

Intermediate 145:N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine

A solution of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate130, 0.829 g, 3.40 mmol), p-toluene sulphonic acid monohydrate (0.924 g,4.86 mmol) and 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 0.8 g,3.24 mmol) was heated at reflux in 2-pentanol (32 mL) under anatmosphere of N₂ for 18 h. The mixture was then allowed to cool, and wasthen concentrated in vacuo. The resulting residue was triturated withCH₃CN until a yellow precipitate formed. This solid was collected byfiltration and was washed with diethyl ether. The solid was suspended in10% CH₃OH in CH₂Cl₂ and washed with saturated aqueous NaHCO₃ (2×)followed by water. The organic solution was then concentrated in vacuo,and the resulting residue was triturated in CH₃CN/water. The mixture wasthen filtered, and the collected solid was washed with CH₃CN followed bydiethyl ether and was then air dried to give the title compound (1.082g, 74%) as a yellow solid; ¹H NMR: 3.90 (3H, s), 4.05 (3H, s), 7.15-7.21(1H, m), 7.26-7.31 (1H, m), 7.36 (1H, d), 7.52 (1H, s), 7.56 (1H, d),8.34 (1H, s), 8.39 (1H, s), 8.40-8.45 (2H, m), 9.20 (1H, s); m/z: ES⁺MH⁺ 454/456.

Intermediate 146:4-Methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 147, 200 mg, 0.40 mmol), iron (134 mg, 2.40 mmol) andNH₄Cl (16 mg, 0.30 mmol), ethanol (18 mL) and water (6 mL) was heated atreflux for 1 h then the mixture was allowed to cool. The mixture wasthen filtered and concentrated in vacuo. The resulting residue wastriturated in 10% CH₃OH in CH₂Cl₂ (15 mL) for 15 minutes and the mixturewas then filtered. The residues were triturated again with 10% CH₃OH inCH₂Cl₂ (15 mL) and the mixture then filtered. The combined filtrateswere washed with brine, dried (Na₂SO₄) and concentrated in vacuo.Purification by FCC, eluting with 2% 7N methanolic ammonia in CH₂Cl₂gave the title compound (144 mg, 77%) as a dark green foam; ¹H NMR:1.66-1.80 (2H, m), 2.06-2.16 (2H, m), 2.42 (3H, s), 2.66 (2H, t), 3.59(2H, d), 3.75 (3H, s), 3.83-3.91 (5H, m), 4.01 (2H, s), 6.30 (1H, s),7.09 (1H, d), 7.16 (1H, t), 7.21-7.28 (1H, m), 7.31 (1H, s), 7.51 (1H,d), 7.70 (1H, s), 8.23 (1H, d), 8.26 (1H, s), 8.43 (1H, d); m/z: ES⁺ MH⁺470.7.

Intermediate 147:N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

A mixture ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129, 300 mg, 0.76 mmol),8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 115 mg, 0.92 mmol),DIPEA (0.158 mL, 0.92 mmol) and DMA (4 mL) was heated at 100° C. for 1h. The mixture was then absorbed onto an SCX column, and the column waswashed with CH₃OH. The column was then eluted with 1:1 methanoic ammoniain CH₂Cl₂ and fractions containing the desired product were combined andconcentrated in vacuo. Purification by FCC, eluting with 1.5% CH₃OH inCH₂Cl₂ gave the title compound (209 mg, 55%) as an orange solid; ¹H NMR:1.71 (2H, dt), 2.00-2.10 (2H, m), 2.40 (3H, s), 2.67 (2H, t), 3.74 (2H,d), 3.88 (3H, s), 3.96 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.12 (1H,t), 7.20 (1H, d), 7.25 (1H, dd), 7.52 (1H, d), 8.02 (1H, s), 8.28-8.34(2H, m), 8.36 (1H, d), 8.63 (1H, s); m/z: ES⁺ MH⁺ 500.6.

Intermediate 148:4-[(3S)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine

A mixture ofN-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 149, 230 mg, 0.47 mmol), iron (158 mg, 2.83 mmol), NH₄Cl(17.7 mg, 0.33 mmol), ethanol (9 mL) and water (3 mL) was heated atreflux for 50 minutes. The reaction was judged to be incomplete sofurther iron (158 mg, 2.83 mmol) and NH₄Cl (17.7 mg, 0.33 mmol) wasadded and the mixture was heated at reflux for a further 0.5h. Aftercooling, the mixture was filtered and concentrated in vacuo.Purification by FCC, eluting with 1.5-7% 7M methanolic ammonia in CH₂Cl₂gave the title compound (187 mg, 87%) as a grey foam; ¹H NMR: 1.78 (1H,m), 2.06 (1H, m), 2.20 (6H, s), 2.86 (1H, d), 2.90-3.01 (2H, m), 3.12(1H, m), 3.15-3.23 (1H, m), 3.76 (3H, s), 3.88 (3H, s), 4.27 (2H, s),6.72 (1H, s), 7.14 (1H, d), 7.15-7.21 (1H, m), 7.22-7.34 (1H, m), 7.50(1H, s), 7.52 (1H, d), 7.74 (1H, s), 8.26 (1H, s), 8.28 (1H, s), 8.43(1H, d); m/z: ES⁺ MH⁺ 458.75.

Intermediate 149:N-{-4-[(3S)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 129, 295 mg, 0.75 mmol),((3S)—N,N-dimethylpyrrolidin-3-amine (103 mg, 0.90 mmol) and DIPEA(0.196 mL, 1.13 mmol) were dissolved in DMA (3 mL) and sealed into amicrowave tube. The mixture was heated to 100° C. for 45 minutes in amicrowave reactor, then cooled to r.t., diluted with CH₃OH and absorbedonto an SCX column. The column was washed with CH₃OH and then elutedwith 1:1 methanolic ammonia in CH₂Cl₂. Fractions containing the desiredproduct were combined and concentrated in vacuo. Purification by FCC,eluting with 2-7% methanolic ammonia in CH₂Cl₂ gave the title compound(235 mg, 64%) as a red solid; ¹H NMR: 1.83 (1H, m), 2.17 (1H, m), 2.22(6H, s), 2.72-2.86 (1H, m), 3.17 (2H, m), 3.26 (1H, m), 3.47 (1H, m),3.88 (3H, s), 3.97 (3H, s), 6.58 (1H, s), 7.12 (1H, t), 7.19 (1H, d),7.21-7.31 (1H, m), 7.52 (1H, d), 8.01 (1H, s), 8.23-8.33 (2H, m), 8.36(1H, d), 8.58 (1H, s); m/z: ES⁻ MH⁺ 488.35.

Intermediate 150:4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A mixture ofN-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 151, 285 mg, 0.56 mmol), iron (188 mg, 3.36 mmol), NH₄Cl(21 mg, 0.39 mmol) ethanol (10.5 mL) and water (3.5 mL) was heated atreflux for 1.5h. The reaction was judged to be incomplete so furtherNH₄Cl (21 mg, 0.39 mmol) and iron (188 mg, 3.36 mmol) were added and themixture was heated at reflux for a further 1.5h. After cooling, themixture was filtered and concentrated in vacuo. Purification by FCC,eluting with 2-10% 7N methanolic ammonia in CH₂Cl₂ gave the titlecompound (183 mg, 69%) as an orange gum which was used without furtherpurification; ¹H NMR: 2.30 (3H, s), 2.36-2.45 (2H, m), 2.60 (2H, t),2.98-3.06 (2H, m), 3.74 (3H, s), 4.34 (2H, s), 5.73 (1H, s), 6.64 (1H,s), 7.09 (1H, m), 7.26 (1H, d), 7.38-7.49 (2H, m), 8.00 (1H, s), 8.35(1H, d), 8.58 (1H, d), 8.80 (2H, m); m/z: ES⁺ MH⁺ 427.

Intermediate 151:N-[2-Methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

A solution of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine(Intermediate 152, 256 mg, 1.00 mmol), p-toluene sulphonic acidmonohydrate (271 mg, 1.43 mmol) and2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline(Intermediate 3, 250 mg, 0.95 mmol) and 2-pentanol (12 mL) was heated atreflux for 4 h under an atmosphere of N₂. The mixture was thenconcentrated in vacuo and the residue was dissolved in CH₃OH. Thissolution was purified by ion exchange chromatography, using an SCXcolumn, eluting with 7M methanolic ammonia. Fractions containing thedesired product were concentrated in vacuo to give a residue that wasdissolved into hot DMF (10 mL). This solution was filtered andconcentrated in vacuo to provide a gum that was triturated with CH₃CN(10 mL) to give the title compound (285 mg, 66%) as a yellow powder; ¹HNMR: 2.36 (5H, s), 2.67 (2H, s), 3.07 (2H, s), 4.02 (3H, s), 5.66 (1H,s), 7.00 (1H, s), 7.12 (1H, t), 7.41 (1H, m), 7.45 (1H, m), 8.45 (2H,t), 8.59 (1H, d), 8.83 (2H, t), 8.90 (1H, s); m/z: ES⁻ M-H⁻ 456.

Intermediate 152: 3-(2-Chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine

K₂CO₃ (5.18 g, 37.50 mmol) was added to 1-aminopyridinium iodide (4.50g, 20.25 mmol) and (E)-2-chloro-4-(2-ethoxyvinyl)pyrimidine(Intermediate 153, 2.77 g, 15 mmol) in DMF (20 mL) at 25° C. Theresulting dark blue suspension was stirred at 25° C. for 15 h (becamedeep blood colour), and then was heated to 110° C. for 2 h. Aftercooling, the mixture was added to water (100 mL) and the resulting brownsolid was collected by filtration, washed with water and dried bysuction. The aqueous filtrate was extracted with EtOAc (2×100 mL) andthe combined organic solutions were washed with water (100 mL×4) andsaturated brine (50 mL). The solution was then dried (MgSO₄) andconcentrated in vacuo. The resulting residue was combined with thepreviously collected brown solid, and dissolved in THF (100 mL). Thissolution was filtered through a 30g silica pad. The eluent wasconcentrated and the resulting residue was washed with −70° C. CH₃OH togive the title compound (1.274g, 37%) as a beige crystalline solid; ¹HNMR: 7.19 (1H, m), 7.65 (1H, m), 7.95 (1H, d), 8.49 (1H, m), 8.61 (1H,d), 8.85-8.91 (1H, m), 8.92 (1H, s); m/z: ES⁺ MH⁺ 231.

Intermediate 153:4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A mixture ofN-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 154, 440 mg, 0.93 mmol), iron (311 mg, 5.56 mmol), NH₄Cl(37.2 mg, 0.70 mmol), ethanol (15 mL) and water (5 mL) was heated atreflux for 1.5h. After cooling the mixture was concentrated in vacuo.The resulting residue was triturated in 10% CH₃OH in CH₂Cl₂ (20 mL) for15 minutes and then filtered. The residues were triturated again with10% CH₃OH in CH₂Cl₂ (10 mL) and then filtered. The combined filtrateswere washed with brine, dried (MgSO₄) and concentrated in vacuo.Purification by FCC, eluting with 0-10% methanolic ammonia in CH₂Cl₂gave the title compound (339 mg, 82%) as a yellow solid aftertrituration with diethyl ether; ¹H NMR: 1.73-1.83 (1H, m), 2.00-2.10(1H, m), 2.20 (6H, s), 2.81-2.90 (1H, m), 2.92-3.00 (2H, m), 3.11-3.16(1H, m), 3.17-3.24 (1H, m), 3.73 (3H, s), 4.28 (2H, br s), 6.71 (1H, s),7.07 (1H, td), 7.20 (1H, d), 7.27 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H,s), 8.30 (1H, d), 8.53 (1H, d), 8.76 (1H, s), 8.79 (1H, d); m/z: ES⁺ MH⁺445.33.

Intermediate 154:N-[4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

(3R)—N,N-Dimethylpyrrolidin-3-amine (0.166 mL, 1.31 mmol) was added to asuspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.227 mL, 1.31 mmol) inDMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. Partpurification was achieved by ion exchange chromatography, using an SCXcolumn, eluting with 7M methanolic ammonia. Clean fractions werecombined and concentrated. Further purification by FCC, eluting with0-7% CH₃OH in CH₂Cl₂ gave the title compound (443 mg, 86%) as an orangesolid; ¹H NMR: 1.77-1.88 (1H, m), 2.13-2.20 (1H, m), 2.23 (6H, s),2.75-2.84 (1H, m), 3.14-3.26 (3H, m), 3.43-3.51 (1H, m), 3.96 (3H, s),6.58 (1H, s), 7.08 (1H, td), 7.27 (1H, d), 7.34-7.39 (1H, m), 8.24 (1H,s), 8.35 (1H, d), 8.40 (1H, s), 8.49 (1H, d), 8.78 (1H, s), 8.80 (1H,d); m/z: ES⁺ MH⁺ 475.31.

Intermediate 155:N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

A mixture of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine(Intermediate 152, 1.476 g, 6.40 mmol),4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 1.310 g, 7.04 mmol),p-toluenesulfonic acid monohydrate (1.339 g, 7.04 mmol) and 2-pentanol(45 mL) was heated at 125° C. for 22 h. After cooling, the mixture wasfiltered. The solid was washed with CH₃OH, diethyl ether and then driedon the filter to give a brown solid. The solid was dissolved in CH₂Cl₂and this solution was washed with sat. NaHCO₃ (×3), water and brine,then dried (MgSO₄) and concentrated in vacuo. The resulting residue wastriturated in boiling CH₃CN and then allowed to cool. The resultingsolid was collected by filtration and air dried to give the titlecompound (1.29 g, 53%) as a brown solid; ¹H NMR: 4.03 (3H, s), 7.11 (1H,td), 7.37 (1H, d), 7.41 (1H, d), 7.43-7.48 (1H, m), 8.45 (1H, d), 8.51(1H, s), 8.58 (1H, d), 8.82-8.84 (2H, m), 9.00 (1H, d); m/z: ES⁺ MH⁺381.54.

Intermediate 156:4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N-(4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A mixture ofN-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 157, 355 mg, 0.77 mmol), iron (258 mg, 4.63 mmol), NH₄Cl(30.9 mg, 0.58 mmol), ethanol (12.6 mL) and water (4.2 mL) was heated atreflux for 1.5h. After cooling the mixture was concentrated in vacuo.The resulting residue was triturated in 10% CH₃OH in CH₂Cl₂ (20 mL) for15 minutes and the mixture was then filtered. The residues weretriturated again with 10% CH₃OH in CH₂Cl₂ (20 mL) and then filtered. Thecombined filtrates were washed with brine, dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-10%methanolic ammonia in CH₂Cl₂ gave the title compound (249 mg, 75%) as abrown solid after trituration with diethyl ether; ¹H NMR: 2.12 (6H, s),3.02-3.09 (1H, m), 3.47 (2H, t), 3.71 (3H, s), 3.98 (2H, t), 4.04 (2H,br s), 6.28 (1H, s), 7.05 (1H, td), 7.09 (1H, s), 7.16 (1H, d),7.36-7.41 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.48 (1H, d), 8.74 (1H,s), 8.77 (1H, d); m/z: ES⁺ MH⁺ 431.35.

Intermediate 157:N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 227 mg,1.31 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-amine(Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.755 mL, 4.36 mmol) inDMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. The mixturewas part-purified by ion exchange chromatography, using an SCX columnand eluting with 7M methanolic ammonia. Clean fractions were combinedand concentrated in vacuo. Further purification by FCC, eluting with0-7% CH₃OH in CH₂Cl₂ gave the title compound (360 mg, 72%) as an orangesolid; ¹H NMR: 2.15 (6H, s), 3.12-3.19 (1H, m), 3.74-3.78 (2H, m), 3.95(3H, s), 4.04-4.09 (2H, m), 6.29 (1H, s), 7.08 (1H, td), 7.28 (1H, d),7.36-7.41 (1H, m), 8.26 (1H, s), 8.35 (1H, d), 8.45-8.49 (2H, m), 8.78(1H, s), 8.80 (1H, d); m/z: ES⁺ MH⁺ 461.33.

Intermediate 158:N¹-(2-Dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,2,4-triamine

A mixture ofN′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,4-diamine(Intermediate 159, 440 mg, 0.95 mmol), iron (319 mg, 5.71 mmol), NH₄Cl(38.2 mg, 0.71 mmol), ethanol (15 mL) and water (5 mL) was heated atreflux for 1.5h. After cooling, the mixture was concentrated in vacuo.The resulting residue was triturated in 10% CH₃OH in CH₂Cl₂ (20 mL) for15 minutes and the mixture was then filtered. The residues weretriturated again with 10% CH₃OH in CH₂Cl₂ (20 mL) and then filtered. Thecombined filtrates were washed with brine, dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-10%methanolic ammonia in CH₂Cl₂ gave the title compound (321 mg, 78%) as abrown gum after trituration with diethyl ether; ¹H NMR: 2.18 (6H, s),2.37 (2H, t), 2.65 (3H, s), 2.91 (2H, t), 3.72 (3H, s), 4.57 (2H, br s),6.77 (1H, s), 7.07 (1H, td), 7.22 (1H, d), 7.29 (1H, s), 7.37-7.42 (1H,m), 7.97 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s), 8.77-8.80(1H, m); m/z: ES⁺ MH⁺ 433.36.

Intermediate 159:N′-(2-Dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,4-diamine

N¹,N¹,N²-trimethylethane-1,2-diamine (138 mg, 1.35 mmol) was added to asuspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 155, 428 mg, 1.13 mmol) and DIPEA (0.234 mL, 1.35 mmol) inDMA (3.3 mL), and the mixture was heated at 85° C. for 1.5h.Part-purification was achieved by ion exchange chromatography, using anSCX column and eluting with 7M methanolic ammonia. Clean fractions werecombined and concentrated in vacuo. Further purification by FCC, elutingwith 0-10% CH₃OH in CH₂Cl₂ gave the title compound (444 mg, 85%) as anorange oil; ¹H NMR: 2.18 (6H, s), 2.50-2.53 (2H, m), 2.87 (3H, s),3.26-3.30 (2H, m), 3.95 (3H, s), 6.86 (1H, s), 7.09 (1H, td), 7.30 (1H,d), 7.35-7.40 (1H, m), 8.27 (1H, s), 8.37 (1H, d), 8.47-8.51 (2H, m),8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES⁺ MH⁺ 463.33.

Intermediate 160:4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]-pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A mixture ofN-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 161, 190 mg, 0.39 mmol), iron (131 mg, 2.34 mmol), NH₄Cl(14.62 mg, 0.27 mmol), ethanol (6 mL) and water (2 mL) was heated atreflux for 4 h and then stirred at r.t. overnight. Part-purification wasachieved by ion exchange chromatography, using an SCX column and elutingwith 7N methanolic ammonia. Appropriate fractions were then concentratedin vacuo onto silica. Purification by FCC, eluting with 0-5% 7Nmethanolic ammonia in CH₂Cl₂ provided impure material. The fractionscontaining desired product were combined and further purified by FCC,eluting with 0-2.5% 7N methanolic ammonia in CH₂Cl₂ to give the titlecompound (100 mg, 56%); m/z: ES⁺ MH⁺ 457.21.

Intermediate 161:N-[4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]-pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

DIPEA (0.343 mL, 1.97 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-snitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 155, 300 mg, 0.79 mmol) and(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole(Intermediate 37, 109 mg, 0.87 mmol) in 2,2,2-trifluoroethanol (5 mL)and the mixture was heated in a microwave at 140° C. for 1 h. Aftercooling, the mixture was part-purified by ion exchange chromatography,using an SCX column and eluting with 7M methanolic ammonia. Appropriatefractions were then concentrated in vacuo onto silica. Furtherpurification by FCC, eluting with 0-4% 7N methanolic ammonia in CH₂Cl₂gave the title compound (198 mg, 52%) as a slightly impure orange/redsolid which was used without further purification; ¹H NMR (CDCl₃): 1.89(1H, dd), 2.06-2.18 (1H, m), 2.21 (3H, s), 2.31 (1H, dd), 2.47 (2H,ddd), 2.65 (1H, t), 2.99-3.10 (1H, m), 3.26 (1H, t), 3.51-3.60 (1H, m),3.98 (3H, s), 4.39-4.46 (1H, m), 6.46 (1H, s), 6.93 (1H, td), 7.04 (1H,d), 7.38 (1H, s), 7.43 (1H, ddd), 8.36 (1H, d), 8.46 (1H, s), 8.52 (1H,m), 8.58 (1H, m), 8.98 (1H, s); m/z: ES⁺ MH⁺ 487.15.

Intermediate 162:4-Methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine

A mixture ofN-[2-methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine(Intermediate 163, 404 mg, 0.83 mmol), iron (278 mg, 4.98 mmol), NH₄Cl(33.3 mg, 0.62 mmol), ethanol (15 mL) and water (5 mL) was heated atreflux for 1.5h. After cooling, the mixture was filtered and theresidues were washed with 1:10 CH₃OH—CH₂Cl₂ (20 mL). The combinedfiltrates were concentrated in vacuo onto silica. Purification by FCC,eluting with 1-10% methanolic ammonia in CH₂Cl₂ gave the title compound(338 mg, 89%) as a yellow solid; ¹H NMR: 1.72 (2H, dt), 2.11 (2H, dd),2.42 (3H, s), 2.66 (2H, t), 3.63 (2H, d), 3.72 (3H, s), 3.87 (2H, d),4.03 (2H, s), 6.29 (1H, s), 7.06 (1H, td), 7.10 (1H, s), 7.16 (1H, d),7.35-7.42 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.52 (1H, d), 8.74 (1H,s), 8.77 (1H, t); m/z: ES⁺ MH⁺ 457.36.

Intermediate 163:N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine

8-Methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 133 mg, 0.88 mmol)was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-amine(Intermediate 155, 280 mg, 0.74 mmol) and DIPEA (0.153 mL, 0.88 mmol) inDMA (3 mL) and the mixture was heated at 100° C. for 1 h. The mixturewas then part-purified by ion exchange chromatography, using an SCXcolumn, eluting with 7M methanolic ammonia. Clean fractions werecombined and concentrated in vacuo. Further purification by FCC, elutingwith 1-8% CH₃OH in CH₂Cl₂ gave the title compound (300 mg) as an orangedry film; ¹H NMR: 1.71 (2H, dt), 2.05 (2H, dd), 2.40 (3H, s), 2.67 (2H,t), 3.75 (2H, d), 3.95 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.09 (1H,td), 7.28 (1H, d), 7.35-7.41 (1H, m), 8.25 (1H, s), 8.36 (1H, d), 8.47(1H, s), 8.50 (1H, d), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES⁺ MH⁺487.30.

Intermediate 164:4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine

Water (4 mL) was added to a stirred mixture ofN-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 165, 286 mg, 0.60 mmol), iron (202 mg, 3.62 mmol), NH₄Cl(22.6 mg, 0.42 mmol) and ethanol (24 mL). The resulting mixture wasstirred at 105° C. for 3 h and was then filtered through diatomaceousearth (Celite™) and concentrated in vacuo. Part-purification by ionexchange chromatography, using an SCX column and eluting with 0.35Mmethanolic ammonia gave the title compound (312 mg, 116%) as a browngum, which was used without further purification; ¹H NMR: 2.13 (2H, d),2.32 (2H, d), 2.80 (6H, d), 2.87-2.98 (2H, m), 3.19 (2H, d), 3.77 (3H,s), 6.74 (1H, s), 7.17 (4H, ddd), 7.46 (1H, d), 7.56 (1H, s), 7.77 (1H,s), 8.28 (2H, dd), 8.43 (1H, d), 11.76 (1H, s); m/z: ES⁺ MH⁺ 444.

Intermediate 165:N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine

(3R)—N,N-Dimethylpyrrolidin-3-amine (92 mg, 0.81 mmol) was added to amixture ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 68, 404 mg, 0.73 mmol) and DIPEA (0.256 mL, 1.46 mmol) inDMA 3 mL. The mixture was then heated in a microwave at 140° C. for0.5h. Part-purification was achieved by ion-exchange chromatography,using an SCX column (20g) and eluting with 0.35M methanolic ammonia.Appropriate fractions were combined and concentrated in vacuo to providean orange/brown gum. This gum was triturated with ethanol (15 mL) togive a solid which was collected by filtration and dried under vacuum togive the title compound (291 mg, 84%) as an orange solid; ¹H NMR: 1.82(1H, dt), 2.12-2.20 (1H, m), 2.22 (6H, s), 2.73-2.83 (1H, m), 3.12-3.22(2H, m), 3.22-3.27 (1H, m), 3.41-3.51 (1H, m), 3.97 (3H, s), 6.58 (1H,s), 7.07 (1H, t), 7.18 (1H, t), 7.26 (1H, d), 7.45 (1H, d), 8.00 (1H,s), 8.28-8.31 (2H, m), 8.35 (1H, d), 8.57 (1H, s), 11.78 (1H, s); m/z:ES⁺ MH⁺ 474.30.

Intermediate 166:4-(3-Dimethylaminoazetidin-1-yl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine

Water (4 mL) was added to a mixture ofN-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 167, 240 mg, 0.52 mmol), iron (175 mg, 3.13 mmol), NH₄Cl(19.56 mg, 0.37 mmol) and ethanol (24 mL). The resulting mixture wasstirred at 105° C. for 3 h, and was then filtered through diatomaceousearth (Celite™). The filtrate was concentrated in vacuo andpart-purified by ion exchange chromatography, using an SCX column andeluting with 0.35M methanolic ammonia. Appropriate fractions werecombined and concentrated in vacuo to give the title compound (241 mg,107%) as a brown gum which was used without further purification; m/z:ES⁺ MH⁺ 430.

Intermediate 167:N-[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine

N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 140 mg,0.81 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 68, 406 mg, 0.74 mmol) and DIPEA (0.514 mL, 2.94 mmol) inDMA (3 mL). The mixture was heated in a microwave at 140° C. for 0.5h.The mixture was then part-purified by ion exchange chromatography, usingan SCX column (20g) and eluting with 0.35M methanolic ammonia.Appropriate fractions were combined nad concentrated in vacuo to providean orange/brown gum. This gum was triturated with ethanol (15 mL) togive a solid which was collected by filtration and dried under vacuum togive the title compound (245 mg, 72%) as an orange solid; ¹H NMR: 2.15(6H, s), 3.17 (1H, dd), 3.76 (2H, dd), 3.97 (3H, s), 4.03-4.10 (2H, m),6.29 (1H, s), 7.08 (1H, t), 7.14-7.21 (1H, m), 7.27 (1H, d), 7.45 (1H,d), 8.01 (1H, s), 8.28-8.37 (3H, m), 8.64 (1H, s), 11.79 (1H, s); m/z:ES⁺ MH⁺ 460.32.

Intermediate 168:N¹-(2-Dimethylaminoethyl)-N⁴-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N¹-methylbenzene-1,2,4-triamine

Water (4 mL) was added in one portion to a mixture ofN′-(2-dimethylaminoethyl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine(Intermediate 169, 270 mg, 0.59 mmol), iron (196 mg, 3.51 mmol), NH₄Cl(21.9 mg, 0.41 mmol) and ethanol (24 mL). The resulting mixture washeated at 105° C. for 3 h then filtered through diatomaceous earth(Celite™). The filtrate was concentrated in vacuo and then part-purifiedby ion exchange chromatography, using an SCX column and eluting with0.35M methanolic ammonia. Appropriate fractions were combined andconcentrated in vacuo to give the title compound (244 mg, 97%) as abrown solid which was used without further purification; ¹H NMR: 2.18(6H, s), 2.37 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.76 (3H, s), 6.77(1H, s), 7.03-7.26 (3H, m), 7.46 (1H, d), 7.52 (1H, s), 7.74 (1H, s),8.18-8.35 (2H, m), 8.42 (1H, d), 11.72 (1H, s); m/z: ES⁺ MH⁺ 432.

Intermediate 169:N′-(2-Dimethylaminoethyl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine

N¹,N¹,N²-Trimethylethane-1,2-diamine (83 mg, 0.82 mmol) was added to amixture ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine(Intermediate 68, 409 mg, 0.74 mmol), DIPEA (0.259 mL, 1.48 mmol) andDMA (3 mL). The resulting mixture was heated in a microwave at 140° C.for 0.5h. Part-purification was achieved by ion exchange chromatography,using an SCX column (20g) and eluting with 0.35 M methanolic ammonia.Appropriate fractions were concentrated in vacuo to provide anorange/brown gum. This gum was triturated with ethanol (15 mL) to give asolid which was collected by filtration and dried under vacuum to givethe title compound (275 mg, 80%) as an orange solid; ¹H NMR: 2.18 (6H,s), 2.45-2.55 (2H, m), 2.87 (3H, s), 3.25-3.30 (2H, m), 3.97 (3H, s),6.87 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.29 (1H, d), 7.46 (1H, d),8.03 (1H, s), 8.33 (3H, dd), 8.66 (1H, s), 11.80 (1H, s); m/z: ES⁺ MH⁺462.34.

Intermediate 170: tert-ButylN-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-(prop-2-enoylamino)phenyl]-methylamino]ethyl]-N-methylcarbamate

Acryloyl chloride (0.069 mL, 0.85 mmol) in CH₂Cl₂ (2.5 mL) was addeddropwise over 5 minutes to a solution of tert-butylN-[2-[[2-amino-5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-methylamino]ethyl]-N-methylcarbamate(Intermediate 171, 377 mg, 0.71 mmol) and DIPEA (0.234 mL, 1.42 mmol) inCH₂Cl₂ (8 mL) cooled in an ice/methanol bath. The mixture was stirredfor 0.5h. The mixture was then diluted with 10% CH₃OH in CH₂Cl₂. Theresulting solution was washed with sat. NaHCO₃, dried (MgSO₄) and thenconcentrated in vacuo. Purification by FCC, eluting with 0-3% CH₃OH inCH₂Cl₂ gave the title compound (325 mg, 78%) as a yellow foam; ¹H NMR:1.38 (9H, s), 2.71 (3H, s), 2.77 (3H, s), 3.00 (2H, t), 3.34 (2H, t),3.88 (3H, s), 3.91 (3H, s), 5.73-5.78 (1H, m), 6.27 (1H, dd), 6.67 (1H,dd), 6.99 (1H, s), 7.17 (1H, t), 7.21-7.27 (2H, m), 7.53 (1H, d), 7.87(1H, s), 8.26 (1H, d), 8.33 (1H, d), 8.62 (1H, s), 8.99 (1H, s), 9.10(1H, s); m/z: ES⁺ MH⁺ 584.73.

Intermediate 171: tert-ButylN-[2-[[2-amino-5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-methylamino]ethyl]-N-methylcarbamate

tert-ButylN-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-nitrophenyl]-methylamino]ethyl]-N-methylcarbamate(Intermediate 172, 428 mg, 0.76 mmol), iron (255 mg, 4.57 mmol) andNH₄Cl (30.6 mg, 0.57 mmol) were heated in ethanol (16 mL) and water(5.33 mL) at reflux for 1.5 h (heating block at 100° C.) and then themixture was cooled and concentrated in vacuo. The resulting residue wastriturated in 10% CH₃OH/CH₂Cl₂ (30 mL) and filtered. The residues weretriturated again with 10% CH₃OH/CH₂Cl₂ (30 mL) and filtered. Thecombined filtrates were washed with brine, dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, eluting with 0-5% CH₃OH inCH₂Cl₂ gave the title compound (380 mg, 94%) as a light brown foam; ¹HNMR: 1.41 (9H, s), 2.64 (3H, s), 2.80 (3H, s), 2.95 (2H, t), 3.34 (2H,t), 3.77 (3H, s), 3.89 (3H, s), 4.40 (2H, s), 6.78 (1H, s), 7.14-7.20(2H, m), 7.23-7.27 (1H, m), 7.52 (1H, d), 7.55 (1H, s), 7.75 (1H, s),8.28 (1H, d), 8.29 (1H, s), 8.42 (1H, d); m/z: ES⁺ MH⁺ 532.37.

Intermediate 172: tert-butylN-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-nitrophenyl]-methylamino]ethyl]-N-methylcarbamate

tert-Butyl N-methyl-N-(2-methylaminoethyl)carbamate (Intermediate 173,300 mg, 1.59 mmol) was added to a suspension ofN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-indol-3-yl)pyrimidin-2-amine(Intermediate 129, 522 mg, 1.33 mmol) and DIPEA (0.462 mL, 2.65 mmol) inDMA (5 mL). The mixture was heated in a microwave at 100° C. for 4 h.The mixture was then diluted with EtOAc and washed with water (5×),brine, dried (MgSO₄) and concentrated in vacuo. Purification by FCC,eluting with 0-2% CH₃OH in CH₂Cl₂ gave the title compound (431 mg, 58%)as an orange solid after trituration with iii diethyl ether; ¹H NMR:1.37 (9H, s), 2.79 (3H, s), 2.88 (3H, s), 3.29-3.36 (2H, m), 3.39-3.44(2H, m), 3.89 (3H, s), 3.99 (3H, s), 6.85 (1H, d), 7.14 (1H, t),7.21-7.28 (2H, m), 7.53 (1H, br d), 8.04 (1H, s), 8.31-8.38 (3H, m),8.72 (1H, br s); m/z: ES⁺ MH⁺ 562.35.

Intermediate 173: tert-Butyl N-methyl-N-(2-methylaminoethyl)carbamate

A solution of di-tert-butyl dicarbonate (4.95 g, 22.69 mmol) in CH₂Cl₂(240 mL) was added dropwise to a stirred solution ofN,N-dimethylethane-1,2-diamine (4 g, 45.38 mmol) in CH₂Cl₂ (80 mL) overa period of 20h. The resulting mixture was stirred at r.t. for 3 h. Themixture was then washed sequentially with sat. Na₂CO₃ (2×100 mL), water(50 mL), and sat. brine (50 mL). The organic solution was dried (MgSO₄)and concentrated in vacuo. Purification by FCC, eluting with 0-10% CH₃OHin CH₂Cl₂ gave the title compound (2.177 g, 51%) as a pale yellow oil;¹H NMR: 1.40 (9H, s), 2.28 (3H, s), 2.57 (2H, t), 2.79 (3H, s), 3.20(2H, t).

Intermediate 174:3-Chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide

To a stirred suspension ofN¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine(Intermediate 175, 33g, 62.29 mmol) and K₂CO₃ (6.09 g, 43.6 mmol) inacetone (300 mL) was added 3-chloropropanoyl chloride (9.78 g, 74.74mmol) at −50° C. The resulting mixture was heated to −20° C. and stirredfor 0.5h. CH₃OH (27.75 mL) and NaOH solution (2.24 g, 56.06 mmol in 300mL water) were added. The resulting mixture was stirred for 3-4 h atr.t. Solid was collected by filtration and dried at 50° C. to give thetitle compound (32.5 g, 95%). ¹H NMR: (CDCl₃) 2.95 (2H, t), 3.04 (6H,d), 3.50 (3H, s), 3.63 (2H, s), 3.81 (2H, t), 4.01 (6H, s), 4.33-4.37(2H, m), 7.33-7.42 (3H, m), 7.47 (1H, t), 7.51-7.55 (1H, m), 8.11-8.21(3H, m), 8.48 (1H, s), 8.87 (1H, s), 9.17 (1H, s); m/z: ES⁺ MH⁺ 536.24.

Intermediate 175:N⁴-(2-Dimethylaminoethyl)-2-methoxy-N⁴-methyl-N¹-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitro-benzene-1,4-diamine

To a stirred solution ofN-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine(Intermediate 176, 65g, 160.28 mmol) andN,N′,N′-trimethyl-ethane-1,2-diamine (19.65 g, 192.3 mmol) in DMA (630mL) was added N-ethyl-N-isopropyl-propan-2-amine (26.93 g, 208.4 mmol)at r.t. The resulting mixture was stirred at 85° C. for 5-6h then cooledto r.t. Water (630 mL) was then added and the mixture was stirred for3-4h. Solid material was collected by filtration, washed with water (315mL) and dried at 50° C. for 12 h to give the title compound (79.4 g,96%) as orange solid; ¹H NMR (CDCl₃): 2.29 (6H, s) 2.60 (2H, t), 2.93(3H, s), 3.31 (2H, t), 3.96 (3H, s), 4.00 (3H, s), 6.69 (1H, s), 7.21(1H, d), 7.30-7.38 (2H, m), 7.43 (1H, d), 7.56 (1H, s), 8.18 (1H, d),8.30 (1H, s), 8.41 (1H, d), 9.59 (1H, s); m/z: ES⁺ MH⁺ 476.23.

Intermediate 176:N-(4-Fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)-pyrimidin-2-amine

1,4-Dioxane (585 mL) was added to a mixture of3-(2-chloropyrimidin-4-yl)-1-methyl-indole (Intermediate 177, 50g,160.04 mmol), 4-fluoro-2-methoxy-5-nitro-aniline (38.03 g, 192.04 mmol)and p-toluenesulfonic acid monohydrate (37.09 g, 192.04 mmol) at r.t.The resulting mixture was stirred at 85° C. for 3 h. After cooling tor.t., the mixture was quenched with 23% aqueous ammonia (39.59 mL, 480.1mmol) and water (195 mL, 510.1 mmol) and a solid precipitated. Theresulting slurry was stirred at r.t. for 3-4 h. The solid was collectedby filtration and dried at 50° C. in vacuo for 12 h to give the titlecompound (74.6 g, 85%) as yellow solid; ¹H NMR (CDCl₃): 4.01 (6H, s),6.90 (1H, d), 7.37-7.48 (4H, m), 8.05-8.12 (2H, m), 8.43 (1H, s), 8.90(1H, s), 9.34 (1H, s); m/z: ES⁺ MH⁺ 394.12.

Intermediate 177: 3-(2-Chloropyrimidin-4-yl)-1-methyl-indole

To a stirred solution 2,4-dichloropyrimidine (70.5 g, 463.76 mmol) indimethoxyethane (900 mL) was added FeCl₃ (77.16 g, 459.12 mmol) and1-methyl indole (68.28 g) at 60° C. The resulting mixture was stirredovernight at 60° C. After cooling, a solid was precipitated by addingmethanol (345 mL) and water (900 mL). The resulting slurry was stirredfor 3 h. The solid was collected by filtration, washed with CH₃OH (1.38L) and dried at 50° C. overnight to give the title compound (138.7 g,81.5%) as a purple solid; ¹H NMR (CDCl₃) 3.89 (3H, s), 7.36-7.41 (3H,m), 7.49 (1H, s), 7.96 (1H, s), 8.34 (1H, s), 8.45 (1H, s); m/z: ES⁺ MH⁺244.05.

Useful crystalline polymorphic forms ofN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide(referred to herein as “Compound X”) and its mesylate salt (referred toherein as “Mesylate Salt Y”) Polymorphic Form A of Compound X

The initially produced Compound X was found to be an amorphous solid.Crystalline polymorphic Form A of Compound X was then prepared by takingsome of this amorphous Compound X (˜20 mg) and slurring it incyclohexane (˜2 mL) at 50° C. while stirring with a magnetic stirrer barfor ˜4 days. Then the sample was allowed to cool, the cap removed fromthe vial, and the sample was left to dry under ambient conditions toprovide Form A of Compound X. The X-ray powder diffraction pattern forForm A of Compound X is shown in FIG. 1. The DSC thermogram of Form A ofCompound X is shown in FIG. 2 which shows an initial event with an onsetat 35.1° C. and a peak at 50.1° C. followed by a subsequent meltingendotherm with an with an onset of 80.2° C. and a peak at 88.3° C.

Polymorphic Form B of Compound X

The initially produced Compound X was found to be an amorphous solid.Crystalline polymorphic Form B of Compound X was then prepared by takingsome of this amorphous Compound X (˜20 mg) and dissolving it in theminimum required amount of EtOAc to achieve full dissolution. Thissolution was then allowed to evaporate to dryness under ambientconditions to provide Form B of Compound X. The X-ray powder diffractionpattern for Form B of Compound X is shown in FIG. 3. The DSC thermogramof Form B of Compound X is shown in FIG. 4 which shows a meltingendotherm with an onset of 94.1° C. and a peak at 113.6° C.

Polymorphic Form C of Compound X

The initially produced Compound X was found to be an amorphous solid.Crystalline polymorphic form C of Compound X was then prepared by takingsome of this amorphous Compound X (˜20 mg) and dissolving it in theminimum amount of diethyl ether required to achieve full dissolution.This solution was then allowed to evaporate to dryness under ambientconditions to provide Form C of Compound X. The X-ray powder diffractionpattern for Form C of Compound X is shown in FIG. 5. The DSC thermogramof Form C of Compound X is shown in FIG. 6 which shows a meltingendotherm with an onset of 91.1° C. and a peak at 103.8° C.

Polymorphic Form D of Compound X

Polymorphic Form D of Compound X, which is believed to be a crystallinemonohydrate form of Compound X, was produced via the method describedabove for Example 28-Alternative syntheses 1 & 2. The X-ray powderdiffraction pattern for Form D of Compound X is shown in FIG. 7. The DSCthermogram of Form C of Compound X is shown in FIG. 8 which shows amelting endotherm with an onset of 108.8° C. and a peak at 117.7° C.Thermogravimetric analysis indicated a weight loss of approximately3.3%. which suggests a monohydrated form (theoretical monohydrate=3.5%).The TGA thermogram is shown in FIG. 9.

Polymorphic Form E of Compound X

Polymorphic Form E of Compound X, which is believed to be a 1.25stoichiometry hydrated form of Compound X, was produced by slurryingCompound X [154g, prepared as described for Example 28 (using acryloylchloride)] in a mixture of methanol (150 mL) and water (600 mL). 10g ofCompound X (Form D) was added and the slurry was stirred at r.t. for 4days. The resulting solid was then collected by filtration and washedwith water and allowed to dry. The X-ray powder diffraction pattern forForm E of Compound X is shown in FIG. 10. The DSC thermogram of Form Eof Compound X is shown in FIG. 11 which shows an initial event with anonset at 66.1° C. and a peak at 77.2° C. followed by a further eventwith an onset at 93.6° C. and a peak at 101.5° C. followed by asubsequent melting endotherm with an with an onset of 130.9° C. and apeak at 135.3° C. Thermogravimetric analysis indicated a weight loss ofapproximately 4.7% which suggests a hydrated form equivalent to a 1.25stoichiometric hydrate. (theoretical 1.25 hydrate=4.3%). The TGAthermogram is shown in FIG. 12.

Polymorphic Form F of Compound X

Polymorphic Form F of Compound X, which is believed to be a 0.25stoichiometry hydrated form of Compound X, was produced by taking someof the Form E of Compound X and drying it in a vacuum oven, at r.t., toconstant weight. The X-ray powder diffraction pattern for Form F ofCompound X is shown in FIG. 13. The DSC thermogram of Form F of CompoundX is shown in FIG. 14 which shows an initial event with an onset at80.9° C. and a peak at 92.8° C. followed by a subsequent meltingendotherm with an with an onset of 130.7° C. and a peak at 135.7° C.Thermogravimetric analysis indicated a weight loss of approximately 0.7%which suggests a partially hydrated form equivalent to a 0.25stoichiometric hydrate. (theoretical 0.25 hydrate=0.89%). The TGAthermogram is shown in FIG. 15.

Polymorphic Form K of Compound X

This polymorphic form of Compound X was produced according to thefollowing method: A solution of acryloyl chloride (0.026 L, 318.48 mmol)in CH₂Cl₂ (290 mL) was added dropwise over 25 minutes to a stirredsuspension ofN¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine(129 g, 289.52 mmol) in CH₂Cl₂ (2.9 L) that was cooled to −5° C. Theaddition is exothermic but the mixture was not permitted to warm to morethan 1° C. during the addition. The resulting mixture was stirred at −5°C. for 2 h. Cold sat. NaHCO₃ solution (1L) was then added dropwise,while keeping the temperature below −2° C. The mixture was then allowedto warm to r.t. The phases were separated, and the resulting organicsolution was washed with water (100 mL) and saturated brine (100 mL).The solution was then dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved into 5% CH₃OH in CH₂Cl₂ (60 mL) and then filtered.The filtered solution was purified by FCC, eluting with 5% CH₃OH inCH₂Cl₂ and clean fractions were combined and concentrated to give impureCompound X as a brown gum (96g). Further purification by chiralpreparative HPLC provided a sample of Compound X which was slurried inCH₃OH (50 mL). Not all of the Compound X material would dissolve. Waterwas then added (250 mL) and the resulting mixture was slurried overnightwith magnetic stirring. The resulting solid was then collected byfiltration and dried in a vacuum oven over a weekend to provide 16.2 gof Compound X in the polymorphic form defined herein as Form K. ¹H NMR:2.20 (6H, s), 2.28 (2H, m), 2.71 (3H, s), 2.88 (2H, m), 3.85 (3H, s),3.90 (3H, s), 5.76 (1H, d), 6.27 (1H, d), 6.43 (1H, m), 7.03 (1H, s),7.15 (1H, m), 7.22 (2H, m), 7.51 (1H, d), 7.87 (1H, s), 8.23 (1H, m),8.33 (1H, m), 8.68 (1H, s), 9.18 (1H, s), 10.16 (1H, s).

The X-ray powder diffraction pattern for Form K of Compound X is shownin FIG. 16. The DSC thermogram of Form K of Compound X is shown in FIG.17 which shows a melting endotherm with an onset of 129.3° C. and a peakat 133.4° C.

Polymorphic Form A of Mesylate Salt Y

Polymorphic Form A of Mesylate Salt Y was prepared by the methoddescribed previously (Example 28A, Procedure 3). The X-ray powderdiffraction pattern for Form A of Mesylate Salt Y is shown in FIG. 18.The DSC thermogram of Form A of Mesylate salt Y is shown in FIG. 19which shows an initial event with an onset at 28.1° C. and a peak at62.2° C. followed by a subsequent melting endotherm with an with anonset of 258.8° C. and a peak at 262.0° C.

Polymorphic Form B of Mesylate Salt Y

Polymorphic Form A of Mesylate Salt Y was prepared by the methoddescribed previously (Example 28A, Procedures 1 and 2). The X-ray powderdiffraction pattern for Form A of Mesylate Salt Y is shown in FIG. 20.The DSC thermogram of Form A of Mesylate salt Y is shown in FIG. 21which shows a melting endotherm with an onset of 245.0° C. and a peak at246.5° C.

1-16. (canceled)
 17. A compound, or a pharmaceutically acceptable saltthereof, wherein the compound isN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.18. A pharmaceutical composition, which comprises the compound accordingto claim 17, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.
 19. Amethod for the treatment of non-small cell lung cancer in a warm-bloodedanimal in need of such treatment, which comprises administering to saidanimal an effective amount of the compound of claim 17, or apharmaceutically acceptable salt thereof.
 20. A compound, wherein thecompound isN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.21. A pharmaceutical composition, which comprises the compound accordingto claim 20, in association with a pharmaceutically-acceptable diluentor carrier.
 22. A method for the treatment of non-small cell lung cancerin a warm-blooded animal in need of such treatment, which comprisesadministering to said animal an effective amount of the compound ofclaim
 20. 23. A mesylate salt ofN-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.24. A pharmaceutical composition, which comprises the mesylate saltaccording to claim 23, in association with a pharmaceutically-acceptablediluent or carrier.
 25. A method for the treatment of non-small celllung cancer in a warm-blooded animal in need of such treatment, whichcomprises administering to said animal an effective amount of themesylate salt of claim
 23. 26. A compound, or a pharmaceuticallyacceptable salt thereof, wherein the compound isN-(4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-[methyl-(2-methylaminoethyl)amino]phenyl)prop-2-enamide.27. A pharmaceutical composition, which comprises the compound accordingto claim 26, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.
 28. Amethod for the treatment of non-small cell lung cancer in a warm-bloodedanimal in need of such treatment, which comprises administering to saidanimal an effective amount of the compound of claim 26, or apharmaceutically acceptable salt thereof.
 29. A compound, wherein thecompound isN-(4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-[methyl-(2-methylaminoethyl)amino]phenyl)prop-2-enamide.30. A pharmaceutical composition, which comprises the compound accordingto claim 29, in association with a pharmaceutically-acceptable diluentor carrier.
 31. A method for the treatment of non-small cell lung cancerin a warm-blooded animal in need of such treatment, which comprisesadministering to said animal an effective amount of the compound ofclaim
 29. 32. A compound, or a pharmaceutically acceptable salt thereof,wherein the compound isN-(2-[2-dimethylaminoethyl-methylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide.33. A pharmaceutical composition, which comprises the compound accordingto claim 32, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.
 34. Amethod for the treatment of non-small cell lung cancer in a warm-bloodedanimal in need of such treatment, which comprises administering to saidanimal an effective amount of the compound of claim 32, or apharmaceutically acceptable salt thereof.
 35. A compound, wherein thecompound isN-(2-[2-dimethylaminoethyl-methylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide.36. A pharmaceutical composition, which comprises the compound accordingto claim 35, in association with a pharmaceutically-acceptable diluentor carrier.
 37. A method for the treatment of non-small cell lung cancerin a warm-blooded animal in need of such treatment, which comprisesadministering to said animal an effective amount of the compound ofclaim 35.